Myocardial infarction before and after the age of 45: Possible role of platelet receptor polymorphisms | Revista Portuguesa de Cardiologia (English edition)

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Pina-Cabral, Virgínia Carvalhais, Bárbara Mesquita, Cláudia Escórcio, Paulo F. Silva, Paula Pinto, Patrícia Napoleão, Teresa Pinheiro, Maria C. Monteiro, António Almeida-Dias, Begoña Criado" "autores" => array:11 [ 0 => array:4 [ "nombre" => "Luís B." "apellidos" => "Pina-Cabral" "email" => array:1 [ 0 => "luispinacabral@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Virgínia" "apellidos" => "Carvalhais" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Bárbara" "apellidos" => "Mesquita" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Cláudia" "apellidos" => "Escórcio" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Paulo F." 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"apellidos" => "Monteiro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 9 => array:3 [ "nombre" => "António" "apellidos" => "Almeida-Dias" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 10 => array:3 [ "nombre" => "Begoña" "apellidos" => "Criado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centro Hospitalar do Médio Ave, Serviço de Cardiologia, Vila Nova de Famalicão, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Centro Hospitalar do Tâmega e Sousa, Hospital Padre Américo, Serviço de Cardiologia, Penafiel, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Instituto de Medicina Molecular, Carlota Saldanha Lab, Lisboa, Portugal" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Universidade de Lisboa, Instituto de Bioengenharia e Biociências (IBB), Departamento de Engenharia e Ciências Nucleares, Portugal" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Enfarte agudo do miocárdio antes e depois dos 45 anos: possível relação com polimorfismos dos recetores plaquetários" ] ] "textoCompleto" => "IntroductionPlatelet receptors are central to physiological platelet responses. They are involved in platelet thrombus formation after vascular injury, being responsible for platelet adhesion to damaged vessel walls and aggregation. Four platelet receptors – glycoprotein (GP) Ib-IX-V, integrin α2β1 (GPIa-IIa), integrin α2bβ3 (GPIIb-IIIa), and the P2Y12 ADP receptor – are crucial for normal hemostasis.<a class="elsevierStyleCrossRefs" href="#bib0240">1–4</a>GPIb-IX-V initiates platelet adhesion to subendothelial von Willebrand factor (vWF) under high shear stress conditions.<a class="elsevierStyleCrossRef" href="#bib0260">5</a> The GPIb subunit is composed of two disulfide-linked polypeptides, alpha and beta. The GPIb alpha subunit contains the binding sites for vWF and alpha-thrombin, both of which activate platelets,<a class="elsevierStyleCrossRef" href="#bib0265">6</a> and is encoded by the GP1BA gene.<a class="elsevierStyleCrossRef" href="#bib0240">1</a>Integrin α2β1 is a specific collagen receptor found in platelets and other cell types that mediates platelet adhesion to collagen following platelet activation.<a class="elsevierStyleCrossRef" href="#bib0270">7</a> It is composed of two subunits, alpha2 and beta1, that are encoded by the ITGA2 and ITGB1 genes, respectively.<a class="elsevierStyleCrossRef" href="#bib0245">2</a>Integrin α2bβ3 plays a pivotal role in platelet aggregation. The major ligands for this glycoprotein are fibrinogen and vWF, and interaction between these ligands and integrin α2bβ3 begins platelet plug formation.<a class="elsevierStyleCrossRef" href="#bib0275">8</a> Integrin alpha2b and beta3 are encoded by the ITGA2B and ITGB3 genes, respectively.<a class="elsevierStyleCrossRef" href="#bib0250">3</a>The purinergic receptor P2Y12 is a Gi-coupled seven-membrane-spanning protein encoded by the P2RY12 gene<a class="elsevierStyleCrossRef" href="#bib0255">4</a> that interacts with ADP.<a class="elsevierStyleCrossRef" href="#bib0255">4</a> ADP stimulates P2Y12-mediated inhibition of adenylyl cyclase and activates intracellular signal transduction pathways that stabilize platelet aggregation.<a class="elsevierStyleCrossRefs" href="#bib0255">4,9</a> The fact that this receptor is the target for prasugrel and clopidogrel, both P2Y12 inhibitors used as antiplatelet therapy for patients with acute coronary syndromes, is of clinical relevance.<a class="elsevierStyleCrossRef" href="#bib0285">10</a>These four platelet membrane receptors present genetic polymorphisms that can affect platelet responsiveness.Three polymorphisms that influence the function and expression of GPIb-IX-V have been described: a variable number of tandem repeats (VNTR) polymorphism; rs6065 (also known as HPA-2); and rs2243093 (Kozak). All of them occur in the GPIb alpha subunit. The VNTR polymorphism, a molecular weight polymorphism within the mucin-like macroglycopeptide region of GPIb alpha, is a 13-amino-acid sequence repeat in which the A allele gives rise to four repeats, B to three repeats, C to two repeats, D to one repeat, and E lacks the 13-amino acid sequence.<a class="elsevierStyleCrossRef" href="#bib0290">11</a> The rs6065 polymorphism is a threonine-to-methionine substitution at position 161 that forms the basis of the HPA-2 platelet alloantigen system.<a class="elsevierStyleCrossRef" href="#bib0295">12</a> The rs2243093 polymorphism is a variation at position -5 from the ATG start codon in which either T or C is present.<a class="elsevierStyleCrossRef" href="#bib0300">13</a>The T allele of the rs938043469 polymorphism (C807T) within the coding region of the alpha2 subunit of integrin α2β1 (GPIa-IIa) is associated with high expression of the receptor and may lead to platelet hyperreactivity, even though this polymorphism does not alter the amino acid sequence of the protein.<a class="elsevierStyleCrossRefs" href="#bib0305">14,15</a>At least nine polymorphisms have been described in the beta3 subunit of integrin α2bβ3. Incompatibility for HPA-1 (PlA) alloantigens is the most common cause of fetal and neonatal alloimune thrombocytopenia in Caucasians.<a class="elsevierStyleCrossRef" href="#bib0315">16</a> The rs5918 polymorphism is a T>C transition creating a missense Leu59Pro variant. Studies on the functional consequences of this polymorphism in thrombotic diseases have yielded conflicting results,<a class="elsevierStyleCrossRefs" href="#bib0320">17,18</a> but an increase in platelet reactivity has been reported in C allele carriers (PlA2) compared with TT genotype individuals (PlA1/A1).<a class="elsevierStyleCrossRef" href="#bib0330">19</a>Various single nucleotide polymorphisms (SNPs) in intron regions of the P2RY12 gene have been described, some of them associated with greater ADP-induced platelet aggregation, including rs2046934 (C>T), rs6801273 (T>C) and rs6798347 (G>A).<a class="elsevierStyleCrossRef" href="#bib0335">20</a>As platelets play an important role in the pathophysiology of myocardial infarction (MI)<a class="elsevierStyleCrossRef" href="#bib0340">21</a> and there is controversy regarding the possible association of platelet polymorphisms and increased cardiovascular risk,<a class="elsevierStyleCrossRef" href="#bib0345">22</a> further studies in specific populations are necessary to clarify the status of this relationship. In this study, we assessed the potential role of eight polymorphisms, one VNTR and seven SNPs, of four genes coding for platelet receptors (GP1BA, ITGB3, ITGA2 and P2RY12) as risk factors for MI. To this end, two groups of patients were analyzed according to the age at which they suffered MI: 45 years or younger (MI ≤45) and more than 45 years (MI >45).MethodsPopulationThe study population included only Portuguese Caucasians. Subjects were divided into three groups: controls, MI ≤45 and MI >45. The control group consisted of 235 subjects (57 male and 178 female) with ages ranging from 15 to 69 years (mean 27 years). The characteristics of the control group have been described previously,<a class="elsevierStyleCrossRef" href="#bib0350">23</a> except for polymorphisms of the ADP receptor gene P2RY12. At the time of blood sample collection, subjects had no clinical signs of hemorrhagic or thrombotic disease. The MI ≤45 group consisted of 44 patients (40 male and four female) who had suffered an MI at or before the age of 45 years, with ages ranging from 27 to 45 years (mean 42 years). The MI >45 group consisted of 78 patients (67 male and 11 female) who had suffered an MI after the age of 45 years, with ages ranging from 51 to 97 years (mean 67 years). Clinical data on smoking status, blood pressure, presence of diabetes, body mass index, family history of cardiovascular disorders and total cholesterol levels were collected for the three groups. All subjects gave their written informed consent to the protocol, which was approved by the local ethics committee.Genotype analysisGenomic DNA was extracted from peripheral blood cells collected by venipuncture in EDTA tubes using a PureLink™ Genomic DNA Mini Kit (Invitrogen). A region containing each polymorphism was amplified by polymerase chain reaction using 1 μg of DNA and 1 μM of specific primers (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Except for the VNTR polymorphism, amplicons were then digested with specific restriction enzymes (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) and the digested fragments were visualized in a 2% ethidium bromide agarose gel.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Statistical analysisGenotype and allelic frequencies for the control group were calculated and Hardy-Weinberg equilibrium was tested for the eight polymorphisms by means of a chi-square test using observed vs. expected genotype frequencies. Genotype frequencies in the MI >45 and MI ≤45 groups were compared with the observed genotype frequencies obtained in the control group using a chi-square test. For chi-square test p values ≤0.05, odds ratios (OR) with 95% confidence intervals (CI) were calculated as estimates of the occurrence of MI as a function of the studied polymorphisms. Binary logistic regression analysis was performed to determine the association between MI and the studied variables through calculation of ORs and their 95% CIs. Adjusted ORs were estimated for genetic and physiological profiles using multinomial logistic regression (adjusted maximum-likelihood estimation). The enter method was selected for entering independent variables into the analysis. IBM SPSS for Windows, version 24.0, was used for all statistical calculations.Results<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> presents the clinical data of the three study groups, and shows statistically significant differences for non-genetic variables. There were significant differences in smoking status (OR 5.651; 95% CI: 2.2472-14.2041; p<0.001), hypertension (OR 16.755; 95% CI: 4.521-62.500; p<0.001), diabetes (OR 60.948; 95% CI: 3.644-1019.274; p=0.004) and obesity (OR 5.6515; 95% CI: 2.2472-14.2041; p<0.001) between the control and MI ≤45 groups. Hypertension (OR 58.823; 95% CI: 17.544-200.000; p<0.001), diabetes (OR 80.119; 95% CI: 4.812-1334.049; p=0.002), obesity (OR 3.472; 95% CI: 1.013-11.905; p=0.048), family history of thrombosis (OR 8.707; 95% CI: 2.657-28.532; p<0.001) and elevated cholesterol (OR 3.891; 95% CI: 1.292-11.765; p<0.016) were significantly different between the control and MI >45 groups. There was also significant heterogeneity in gender distribution in the MI groups, with a larger proportion of males in both groups (p<0.001 for both).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Genotypes were in Hardy-Weinberg equilibrium for all polymorphisms in the control group. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the genotype frequencies for the eight polymorphisms in the three study groups and the p values obtained when the MI groups were compared with the control group for each polymorphism. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> also shows the same comparison between groups but adding the homozygotic and heterozygotic genotypes for the allele considered of higher risk. This association of genotypes was performed due to the low numbers of patients with some genotypes. As can be seen, the p values for the rs5918 polymorphism of integrin beta3 were not significant, meaning that there were no statistical differences between the control and MI groups (p=0.579 and p=0.359 for MI >45 and p=0.407 and p=0.722 for MI ≤45).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>There was also no statistically significant difference between the control and MI groups for GPIb alpha polymorphisms. The p value for the rs2243093 polymorphism was 0.104 when MI ≤45 was compared with the control group. It is important to note that for this polymorphism only one homozygote (CC) was found, corresponding to one control individual. For the rs6065 polymorphism, as in the previous case, although the prevalence of CT heterozygotes was higher in MI ≤45 (26.2%) compared with the control group (18.5%), the chi-square test was not statistically significant (p=0.199). No homozygotes (TT) were found for this polymorphism in all of the study population. When the control group was divided into two subpopulations by age (control ≤45 years and control >45 years) and only males were included, rs6065 was the only polymorphism that showed a statistical difference: p<0.001 for control ≤45, males only (n=44) compared with MI ≤45, males only (n=38). The phenotype distribution was 41 CC and 3 CT for control ≤45, males only and 27 CC and 11 CT for MI ≤45, males only. When ORs were calculated for CT vs. CC genotypes in MI ≤45, males only, the p value was 0.016 (OR 5.568; 95% CI: 1.421-21.822). No adjusted ORs were calculated due to the low numbers in these subgroups (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>With respect to the other GPIb alpha polymorphism studied, VNTR, no differences were found in chi-square tests (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). In our study population, no A allele for VNTR was found.For the integrin alpha2 polymorphism rs938043469, a significant difference was found in the p value when the MI >45 group was compared with the control group (p=0.011). This difference was mainly due to a greater proportion of TT homozygotes (19.2% in MI >45 vs. 9.9% in controls) and fewer CC homozygotes (28.2% in MI >45 vs. 38.7% in controls) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). Accordingly, the OR for MI >45 was significantly higher in TT vs. CC genotypes (OR 2.662, CI: 1.181-6.001, p=0.027) (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). After adjustment, the OR remained statistically significant, meaning that patients with a TT genotype have a greater risk of MI after the age of 45 years independently of other variables (OR 2.852, 95% CI: 1.092-7.451, p=0.032) (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). No differences were found between the control and MI ≤45 groups for this polymorphism. When both patient groups were compared by means of binary logistic regression analysis, patients with the TT genotype were more likely to suffer MI after the age of 45 years (OR 4.528, 95% CI: 1.047-19.576, p=0.043).For the three P2RY12 polymorphisms studied, there was a significant difference in rs2046934 when the MI >45 and control groups were compared in terms of associated genotypes, AG+GG (p=0.043). This difference was due to a greater proportion of heterozygotes in the MI >45 group compared with controls. However, when ORs were calculated comparing the AA and AG+GG genotypes, the difference was not statistically significant (OR 1.665, CI: 0.933-2.970, p=0.090) (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).DiscussionIn this study, we analyzed the effect of several platelet gene polymorphisms in patients who had suffered MI. These patients were divided into two groups according to the age at which they suffered MI: 45 years or younger and more than 45 years.According to our results, the only polymorphism significantly associated with an increased risk for MI in the overall study population was rs938043469 in the alpha2 subunit (GPIa) of integrin α2β1. We also concluded that the presence of the T allele in homozygosity is essential for this increased risk of MI. Nevertheless, the rs938043469 polymorphism does not appear to influence early onset of MI, since the results for the MI ≤45 group showed no correlation between the presence of this polymorphism and MI (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The frequency of the TT genotype in the control group (9.9%) was within the range of previous reports.<a class="elsevierStyleCrossRefs" href="#bib0355">24–26</a> The proportion of the TT genotype in the MI >45 group (19.2%) was higher than in the control group. Since Kunicki et al. first described this polymorphism in 1997,<a class="elsevierStyleCrossRef" href="#bib0370">27</a> several studies have assessed the relationship between the polymorphism and cardiovascular disease, mainly in younger adults, with conflicting results.<a class="elsevierStyleCrossRefs" href="#bib0360">25,28</a> In 2007, a meta-analysis of published data regarding the role of rs938043469 in coronary artery disease (CAD) concluded that there was no association between this polymorphism and CAD.<a class="elsevierStyleCrossRef" href="#bib0380">29</a> Nevertheless, our results were very similar to those of Jian-Xia Lu et al. in Chinese patients who had suffered ischemic stroke,<a class="elsevierStyleCrossRef" href="#bib0355">24</a> despite the differences in ethnicity and cardiovascular diseases. Moreover, a recent meta-analysis found that the T allele or TT genotype of the rs938043469 polymorphism were associated with increased risk for ischemic stroke.<a class="elsevierStyleCrossRef" href="#bib0385">30</a>Although a silent polymorphism, rs938043469 is believed to influence the density of integrin α2β1 (GPIa-IIa) in the platelet membrane, with the T allele being responsible for the highest expression of the glycoprotein.<a class="elsevierStyleCrossRefs" href="#bib0305">14,15</a> This variation in receptor density may account for greater platelet responsiveness to collagen in the TT genotype, enhancing the thrombotic potential of platelets in pathological states. However, it should be remembered that this receptor, despite its importance for platelet adhesion to subendothelial collagen, particularly in static conditions, is not physiologically as important as GPIb-V-IX for the initiation of adhesion to subendothelial tissue in conditions of high shear stress as found in the arterial circulation.<a class="elsevierStyleCrossRef" href="#bib0390">31</a> This may explain the difficulty in finding statistically significant evidence for the role of this polymorphism in certain cardiovascular diseases. The conflicting results found may also reflect different study designs, patients and diseases<a class="elsevierStyleCrossRefs" href="#bib0355">24–26,28,30</a> and the difficulty in establishing that a single polymorphism is in itself crucial to such a complex and multifactorial event as MI.In many studies, including the present one, some results may fail to reach statistical significance, and as a result it may be impossible to decide definitively whether a particular association exists. Nevertheless, in our opinion, such results should not necessarily be disregarded, but should be analyzed carefully in order to determine their biological significance. Examples of such results are those concerning the rs2243093, rs6065, VNTR and rs2046934 polymorphisms in our MI groups.Analysis of the rs2243093 polymorphism revealed a higher proportion of the TC genotype in the MI ≤45 group than in controls and the chi-square test was very close to significance (p=0.104). A similar result was found in two studies in which the rs2243093 polymorphism was associated with an increased risk of ischemic stroke.<a class="elsevierStyleCrossRefs" href="#bib0395">32,33</a> In these studies, a higher frequency of the TC genotype was reported.<a class="elsevierStyleCrossRefs" href="#bib0395">32,33</a> Another study associating the rs2243093 polymorphism and risk of CAD published in 2015 by Zhang et al. found a high frequency of the CC genotype and concluded that this genotype is a biomarker of genetic susceptibility.<a class="elsevierStyleCrossRef" href="#bib0405">34</a> Interestingly, there was only one individual with the CC genotype in our control group, corresponding to a frequency of 0.4% in the overall population, which is within the range of other populations.<a class="elsevierStyleCrossRef" href="#bib0300">13</a> This polymorphism lies in the 5′ UTR of the GP1BA gene, where a T or a C may be present in position -5 from the ATG start codon. The C allele has been associated with increased expression of the receptor on the cell membrane,<a class="elsevierStyleCrossRef" href="#bib0300">13</a> which may explain the link between this polymorphism and greater likelihood of arterial thrombus formation in some vascular pathologies, due to increased platelet adhesiveness. Nevertheless, our results did not show a clear correlation between the Kozak polymorphism and MI in any of the MI groups studied.In the rs6065 polymorphism, threonine or methionine is found at position 161 of GPIb alpha due to a C1018T nucleotide change.<a class="elsevierStyleCrossRef" href="#bib0410">35</a> rs6065 is of clinical importance because it is implicated in neonatal alloimmune thrombocytopenic purpura, post-transfusion purpura, and refractoriness to HLA-matched platelet transfusion.<a class="elsevierStyleCrossRef" href="#bib0415">36</a> The presence of methionine has been associated with increased risk for MI and CAD in several studies.<a class="elsevierStyleCrossRefs" href="#bib0405">34,37</a> However, in a study of the functional effects of this polymorphism in 2003, Ulrichts et al. described a stronger interaction between the GPIb alpha subunit and vWF in glycoproteins that carry threonine (C allele) than methionine (T allele).<a class="elsevierStyleCrossRef" href="#bib0425">38</a> This finding does not agree with the above results. Nevertheless, as the authors point out in their paper, vWF binding to GPIb alpha was investigated in a stationary state and not in the shear stress conditions usually seen in a vascular stenosis.<a class="elsevierStyleCrossRef" href="#bib0425">38</a> We found a higher percentage of CT heterozygotes in the MI ≤45 group than in the control group, while in the MI >45 group no differences were found from the control group. These results, although not statistically significant, are in agreement with the findings of Mikkelsson et al., who reported a correlation between the presence of Met161 and sudden cardiac death in men aged less than 55 years.<a class="elsevierStyleCrossRef" href="#bib0420">37</a> Interestingly, when we reanalyzed the statistics including only men in the control ≤45 and MI ≤45 groups, there was a significant difference (p<0.001) in genotype distribution, with a higher percentage of heterozygotes in MI ≤45 compared with control ≤45. This result, despite the low numbers involved, especially in control ≤45, highlights the possible contribution of the rs6065 polymorphism to early MI.For the VNTR polymorphism in GPIb alpha, no A allele (four repeats) and one rare E allele, which has only been reported in Caucasians, were found in our study groups.<a class="elsevierStyleCrossRef" href="#bib0430">39</a> The A allele has been reported mainly in Japanese and Native American populations.<a class="elsevierStyleCrossRef" href="#bib0435">40</a> The most interesting result that we observed regarding this polymorphism was the higher frequency of the BC genotype in MI ≤45 than in the control and MI >45 groups. However, the p value was not significant. This may be due to the large number of classes (six genotypes) and the small sample size, especially in the MI ≤45 group. The literature often attributes a protective role to the CC genotype,<a class="elsevierStyleCrossRef" href="#bib0440">41</a> and it should be noted that that the CC genotype was more frequent in the control group than in the MI >45 and MI ≤45 groups. Studies assessing the physiological response of each of the different sized GPIb alpha subunits are needed. In one attempt to help clarify this issue we conducted a study in which platelets with different VNTR genotypes were subjected to PFA-100® testing using collagen/ADP and collagen/epinephrine cartridges and occlusion time was measured. Our preliminary results showed that platelets with the CC genotype take longer to occlude the cartridge than platelets bearing a B allele (BC or BD), supporting its previously reported protective role (data not shown).The p value for the rs2046934 polymorphism was statistically significant. This difference was found when AG and GG genotypes were associated and, as in the C807T polymorphism, the difference was seen in the MI >45 group. When associated, the difference was due to a greater number of heterozygotes in the MI >45 than in the control group. rs2046934 is an intronic polymorphism that does not alter the amino acid sequence of the protein and is in linkage disequilibrium with other polymorphisms that also do not change the protein structure of the receptor. All these polymorphisms form the H2 haplotype of the P2RY12 gene.<a class="elsevierStyleCrossRef" href="#bib0335">20</a> In aggregometry tests, the H2 haplotype was associated with higher maximal aggregation in response to ADP than the H1 haplotype.<a class="elsevierStyleCrossRef" href="#bib0335">20</a> This result suggests a possible relationship between the H2 haplotype and atherothrombosis. However, a study by Amisten et al. found no association between the H2 haplotype and MI.<a class="elsevierStyleCrossRef" href="#bib0445">42</a> In the present study, although there were differences in the chi-square test result, the p value of an odds ratio test calculated for AG+GG vs. AA genotypes in the MI >45 group was not statistically significant. In a recent study assessing the effects of platelet polymorphisms on antiplatelet drug responsiveness and clinical outcomes in patients with acute minor ischemic stroke that included the P2RY12 gene, the authors did not find that any of the P2RY12 polymorphisms that we also studied had a pathophysiological effect.<a class="elsevierStyleCrossRef" href="#bib0450">43</a> Additional studies should be conducted to elucidate the pathophysiological role, if any, of the rs2046934 polymorphism. For the other P2RY12 polymorphisms studied no statistical differences were found.The rs5918 polymorphism showed no correlation or trend with MI in any MI group. Although several studies have suggested an association between PlA2 (the C allele) and arterial events,<a class="elsevierStyleCrossRefs" href="#bib0455">44,45</a> we found no statistical correlation between this polymorphism and MI, as also reported in several other studies,<a class="elsevierStyleCrossRefs" href="#bib0465">46,47</a> and controversy remains concerning the relationship between this polymorphism and cardiovascular pathology.The results of the present work, despite its inherent limitations, particularly a limited number of patients in our MI groups and the heterogeneity between controls and MI patient groups, provide important hints on the possible role of platelet receptor polymorphisms in thrombotic disease. The most important conclusion of our work is that the TT genotype of the rs938043469 polymorphism of integrin alpha2 (GPIa) is significantly associated with the presence of MI in patients older than 45 years. Further studies with larger and more homogenous cohorts may support our findings and help to clarify the role of the rs6065 and rs2046934 polymorphisms and their association with MI. It is important to point out that the two groups of MI patients also differ in non-genetic variables, and so further studies are required to understand the molecular pathways associated with the polymorphisms under study. In addition, the association between these polymorphisms and clinical outcomes should be studied to enable better stratification of MI patients according to their genetic profile.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1270125" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1175469" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1270124" "titulo" => "Resumo" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1175470" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Population" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Genotype analysis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 9 => array:2 [ "identificador" => "xack435929" "titulo" => "Acknowledgments" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-05-24" "fechaAceptado" => "2018-03-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1175469" "palabras" => array:4 [ 0 => "Myocardial infarction and platelet polymorphisms" 1 => "GPIb-V-IX" 2 => "GPIa-IIa" 3 => "GPIIb-IIIa: ADP P2Y12 receptor" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec1175470" "palabras" => array:5 [ 0 => "Enfarte agudo do miocárdio e polimorfismos plaquetários" 1 => "GP Ib-V-IX" 2 => "GP Ia-IIa" 3 => "GP IIb-IIIa" 4 => "ADP P2Y12 receptor" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionWe examined the potential role of polymorphisms of the platelet genes GP1BA (rs2243093, rs6065 and VNTR), ITGB3 (rs5918), ITGA2 (rs938043469) and P2RY12 (rs2046934, rs6801273 and rs6798347) as risk factors for myocardial infarction (MI). MethodsThe study population was divided into three groups: controls (n=235), MI at age ≤45 years (MI ≤45, n=44), and MI at age >45 years (MI >45, n=78). The control group was further divided into two subgroups (control ≤45 and >45), and subgroups including only men were also considered for statistical analysis. Polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism analysis. ResultsRegarding non-genetic risk factors, the control group differed statistically from the MI ≤45 group (p<00.5) in terms of smoking, hypertension, diabetes and obesity, and from the MI >45 group (p<0.05) in terms of hypertension, diabetes, obesity, family history of thrombosis and high cholesterol. For the studied ITGA2 polymorphism, a statistical difference was found when MI >45 was compared with the control group, with a higher risk of MI in the TT genotype (OR 2.852; 95% CI: 1.092-7.451; p=0.032). In the GP1BA rs6065 polymorphism, a statistically significant difference was found between control ≤45 only men and MI ≤45 only men, with a higher risk in the CT genotype (OR 5.568; 95% CI: 1.421-21.822; p=0.016), despite the low numbers included. The other polymorphisms studied did not show any statistically significant correlations. ConclusionThere is a statistically significant association between the TT genotype of the ITGA2 rs938043469 polymorphism and increased risk for MI >45." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "IntroduçãoDeterminou-se o papel de polimorfismos dos genes de expressão plaquetária GP1BA (rs2243093, rs6065 e o VNTR p.Ser415_Thr428(0_4)), ITGB3 (rs5918), ITGA2 (rs938043469) e P2RY12 (rs2046934, rs6801273 e rs6798347) como fatores de risco para o enfarte agudo do miocárdio (EAM). MétodosA amostra foi dividida em três grupos: Controlo (n=235), EAM ≤45 anos (n=44) e EAM >45 anos (n=78). O grupo Controlo foi ainda dividido em dois subgrupos (Controlo ≤45 e >45). Subgrupos incluindo somente homens também foram considerados para fins estatísticos. Os polimorfismos foram estudados através de PCR e RFLP. ResultadosEm relação aos fatores de risco não genéticos, o grupo Controlo diferia estatisticamente do grupo EAM ≤ 45 anos (p<0,05) em termos de hábitos tabágicos, hipertensão, diabetes e obesidade e também diferia do grupo EAM >45 anos (p<0,05) nas variáveis hipertensão, diabetes, obesidade, antecedentes familiares de trombose e colesterol. Para o polimorfismo estudado do gene ITGA2, verificou-se uma diferença estatisticamente significativa quando se compararam os grupos EAM >45 anos e Controlo, associando-se o genótipo TT a aumento de risco de EAM (OR 2,852; IC 95% de 1,092 a 7,451; p=0,032). No polimorfismo rs6065 do gene GP1BA foi encontrada uma diferença estatística quando comparados os grupos Controlo ≤ 45 só homens e EAM ≤ 45 só homens, associando-se o genótipo C/T a um maior risco de EAM (OR 5,568; IC 95% de 1,421 a 21,822; p=0,016), apesar do baixo n. Os outros polimorfismos não apresentaram correlação significativa. ConclusãoExiste uma associação estatística significativa entre o genótipo T/T do polimorfismo rs938043469 do gene ITGA2 e o risco de EAM >45." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusão" ] ] ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Platelet receptor \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Polymorphism \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Primers \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Restriction enzymes \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">α2bβ3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ITGB3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs5918 (PlA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-GGACTTCTCTTTGGGCTCCTR-CTGTCTCCAGAGCCCTTGTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MspII \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">Ib-V-IX</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">GP1BA</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2243093 (Kozak) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-AGGGGGATCCACTCAAGGR-AGGCGAGTGTAAGGCATCAG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BsuRI \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6065 (HPA-2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-GCCAGCCACCTAGAAGTGAAR-AAAAGCAAAAGGCAGGAGGT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lwel \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VNTR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-CTGGAGCCCACTCCAAGCR-TTGTGGCAGACACCAGGAT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">α2β1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ITGA2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs938043469 (C807T) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-CTACCGGCCCATGTCTAAATR-TCTTTGTCTTTTCCTTACTTTTTCA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hpy188I \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">P2Y12</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">P2RY12</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2046934 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-TGCTGAAAATTGAAGCCATACR-CAAAACAGGGCATACTTTCCA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HpyCH4IV \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6801273 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-TTGTTGAAATATCAGAAAATGTGAGR-AGTCCACCTGCTGCTATTGA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bsh1236I \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6798347 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F-TGATGTAAGTGGGGAAAGGAAR-CAAGTTTCAAACCCGAGGAA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BseGI \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2172759.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Primers and restriction enzymes used for genotype discrimination." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "The chi-square test was used to compare variables between the control and MI groups.BMI: body mass index; MI ≤45: myocardial infarction at or before the age of 45 years; MI >45: myocardial infarction after the age of 45 years." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Controls (n=235) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MI ≤45 (n=44) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MI >45 (n=78) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Male gender, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 (24.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 (90.9)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 (85.9)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Active smokers, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 (26.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 (68.2)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 (34.6) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypertension, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (3.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 (36.4)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54 (69.2)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetes, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 (22.7)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (28.2)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Obesity (BMI >30 kg/m2), n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (3.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (25.0)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">19 (24.4)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Family history of thrombosis, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">107 (45.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 (56.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (7.7)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total cholesterol >200 mg/dl, n (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">59 (25.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (25.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43 (55.1)<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2172758.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "p<0.05 compared to control group." ] ] ] "descripcion" => array:1 [ "en" => "Clinical characteristics of the study population." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "MI ≤45: myocardial infarction at or before the age of 45 years; MI >45: myocardial infarction after the age of 45 years." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Polymorphism genotypes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Controls, n (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MI >45, n (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MI ≤45, n (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p<a class="elsevierStyleCrossRef" href="#tblfn0015">b</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs5918 TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">144 (69.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57 (74.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.579</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 (66.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.407</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs5918 TC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">55 (26.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 (23.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (33.3) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs5918 CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (4.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (2.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs5918 TC+CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 (30.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 (26.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.359 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (33.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.722 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2243093 TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">168 (78.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 (80.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.778</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29 (69.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.104</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2243093 TC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44 (20.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (19.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (31.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2243093 CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (0.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2243093 TC+CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 (21.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (19.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.728 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13 (31.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.118 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6065 CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">172 (81.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 (80.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.825</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 (73.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.199</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6065 CT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 (18.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (19.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (26.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6065 TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6065 CT+TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">39 (18.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (19.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.825 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (26.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.199 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VNTR BC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">35 (16.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 (15.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="char" valign="middle">0.373</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (27.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="char" valign="middle">0.236</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VNTR BD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (0.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (1.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VNTR CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">153 (70.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49 (65.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 (62.2) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VNTR CD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 (11.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 (15.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (10.8) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VNTR CE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (0.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VNTR D/D \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (0.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (1.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 (0.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs938043469 CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">82 (38.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (28.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.011<a class="elsevierStyleCrossRef" href="#tblfn0020">c</a></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 (45.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.654</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs938043469 CT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">109 (51.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 (52.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 (45.5) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs938043469 TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21 (9.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (19.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 (9.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs938043469 CT+TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">130 (61.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56 (71.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.057 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 (54.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.358 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2046934 AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">177 (75.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">44 (64.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.118</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 (72.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.197</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2046934 AG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 (22.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (32.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9 (20.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2046934 GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 (2.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (2.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (7.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2046934 AG+GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">58 (24.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 (35.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.043<a class="elsevierStyleCrossRef" href="#tblfn0020">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 (27.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.238 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6801273 TT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">86 (36.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 (38.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.331</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">18 (41.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.608</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6801273 TC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">123 (52.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31 (45.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22 (51.1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6801273 CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 (11.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (16.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 (7.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6801273 TC+CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">149 (63.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">42 (61.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.780 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 (58.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.474 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6798347 GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">152 (64.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">41 (59.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.175</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">26 (60.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="char" valign="middle">0.828</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6798347 GA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 (30.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">27 (39.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 (34.9) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6798347 AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">11 (4.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 (1.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 (4.7) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6798347 GA+AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">83 (35.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">28 (40.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.359 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (39.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.561 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2172756.png" ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "By chi-square test between controls and MI >45." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "By chi-square test between controls and MI ≤45." ] 2 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "c" "nota" => "p≤0.05." ] ] ] "descripcion" => array:1 [ "en" => "Genotype frequencies for the rs5918 (PlA), rs2243093 (Kozak), rs6065 (HPA-2), VNTR, rs938043469 (C807T), P2Y12 rs2046934, P2Y12 rs6801273 and P2Y12 rs6798347 polymorphisms." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CI: confidence interval; MI ≤45: myocardial infarction at or before the age of 45 years; MI >45: myocardial infarction after the age of 45 years; OR: odds ratio." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Genotypes \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adjusted OR (95% CI) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">p<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs938043469 (controls vs. MI >45) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TT vs. CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.662 (1.181-6.001) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.027<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.852 (1.092-7.451) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.032<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs2046934 (controls vs. MI >45) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">AG+GG vs. AA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.665 (0.933-2.970) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.090 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">rs6065 (controls ≤45 vs. MI ≤45, males only) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CT vs. CC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5.568 (1.421-21.822) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.016<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2172757.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "Adjusted for the non-genetic variables and the other polymorphisms studied." ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "b" "nota" => "p<0.05." ] ] ] "descripcion" => array:1 [ "en" => "Odds ratios of polymorphisms that showed a statistically significant chi-square test." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:47 [ 0 => array:3 [ "identificador" => "bib0240" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The glycoprotein Ib-IX-V complex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.K. Andrews" 1 => "M.C. Berndt" 2 => "J.A. López" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "A.D.Michelson" "titulo" => "Platelets" "paginaInicial" => "145" "paginaFinal" => "163" "edicion" => "2nd ed." "serieFecha" => "2007" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0245" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Platelet receptors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.J. Clemetson" 1 => "J.M. Clemetson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:6 [ "editores" => "A.D.Michelson" "titulo" => "Platelets" "paginaInicial" => "117" "paginaFinal" => "143" "edicion" => "2nd ed." 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Original Article

Myocardial infarction before and after the age of 45: Possible role of platelet receptor polymorphisms

Enfarte agudo do miocárdio antes e depois dos 45 anos: possível relação com polimorfismos dos recetores plaquetários

Luís B. Pina-Cabrala,

Corresponding author

luispinacabral@hotmail.com

Corresponding author.

, Virgínia Carvalhaisa, Bárbara Mesquitaa, Cláudia Escórcioa, Paulo F. Silvab, Paula Pintoc, Patrícia Napoleãod, Teresa Pinheiroe, Maria C. Monteiroa, António Almeida-Diasa, Begoña Criadoa

a Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal

b Centro Hospitalar do Médio Ave, Serviço de Cardiologia, Vila Nova de Famalicão, Portugal

c Centro Hospitalar do Tâmega e Sousa, Hospital Padre Américo, Serviço de Cardiologia, Penafiel, Portugal

d Instituto de Medicina Molecular, Carlota Saldanha Lab, Lisboa, Portugal

e Universidade de Lisboa, Instituto de Bioengenharia e Biociências (IBB), Departamento de Engenharia e Ciências Nucleares, Portugal

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        "titulo" => "Enfarte agudo do mioc&#225;rdio antes e depois dos 45 anos&#58; poss&#237;vel rela&#231;&#227;o com polimorfismos dos recetores plaquet&#225;rios"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Platelet receptors are central to physiological platelet responses&#46; They are involved in platelet thrombus formation after vascular injury&#44; being responsible for platelet adhesion to damaged vessel walls and aggregation&#46; Four platelet receptors &#8211; glycoprotein &#40;GP&#41; Ib-IX-V&#44; integrin &#945;2&#946;1 &#40;GPIa-IIa&#41;&#44; integrin &#945;2b&#946;3 &#40;GPIIb-IIIa&#41;&#44; and the P2Y<span class="elsevierStyleInf">12</span> ADP receptor &#8211; are crucial for normal hemostasis&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">1&#8211;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">GPIb-IX-V initiates platelet adhesion to subendothelial von Willebrand factor &#40;vWF&#41; under high shear stress conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">5</span></a> The GPIb subunit is composed of two disulfide-linked polypeptides&#44; alpha and beta&#46; The GPIb alpha subunit contains the binding sites for vWF and alpha-thrombin&#44; both of which activate platelets&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">6</span></a> and is encoded by the <span class="elsevierStyleItalic">GP1BA</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Integrin &#945;2&#946;1 is a specific collagen receptor found in platelets and other cell types that mediates platelet adhesion to collagen following platelet activation&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">7</span></a> It is composed of two subunits&#44; alpha2 and beta1&#44; that are encoded by the <span class="elsevierStyleItalic">ITGA2</span> and <span class="elsevierStyleItalic">ITGB1</span> genes&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Integrin &#945;2b&#946;3 plays a pivotal role in platelet aggregation&#46; The major ligands for this glycoprotein are fibrinogen and vWF&#44; and interaction between these ligands and integrin &#945;2b&#946;3 begins platelet plug formation&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">8</span></a> Integrin alpha2b and beta3 are encoded by the <span class="elsevierStyleItalic">ITGA2B</span> and <span class="elsevierStyleItalic">ITGB3</span> genes&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The purinergic receptor P2Y<span class="elsevierStyleInf">12</span> is a Gi-coupled seven-membrane-spanning protein encoded by the <span class="elsevierStyleItalic">P2RY12</span> gene<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">4</span></a> that interacts with ADP&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">4</span></a> ADP stimulates P2Y<span class="elsevierStyleInf">12</span>-mediated inhibition of adenylyl cyclase and activates intracellular signal transduction pathways that stabilize platelet aggregation&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">4&#44;9</span></a> The fact that this receptor is the target for prasugrel and clopidogrel&#44; both P2Y<span class="elsevierStyleInf">12</span> inhibitors used as antiplatelet therapy for patients with acute coronary syndromes&#44; is of clinical relevance&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">These four platelet membrane receptors present genetic polymorphisms that can affect platelet responsiveness&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Three polymorphisms that influence the function and expression of GPIb-IX-V have been described&#58; a variable number of tandem repeats &#40;VNTR&#41; polymorphism&#59; rs6065 &#40;also known as HPA-2&#41;&#59; and rs2243093 &#40;Kozak&#41;&#46; All of them occur in the GPIb alpha subunit&#46; The VNTR polymorphism&#44; a molecular weight polymorphism within the mucin-like macroglycopeptide region of GPIb alpha&#44; is a 13-amino-acid sequence repeat in which the A allele gives rise to four repeats&#44; B to three repeats&#44; C to two repeats&#44; D to one repeat&#44; and E lacks the 13-amino acid sequence&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">11</span></a> The rs6065 polymorphism is a threonine-to-methionine substitution at position 161 that forms the basis of the HPA-2 platelet alloantigen system&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">12</span></a> The rs2243093 polymorphism is a variation at position -5 from the ATG start codon in which either T or C is present&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The T allele of the rs938043469 polymorphism &#40;C807T&#41; within the coding region of the alpha2 subunit of integrin &#945;2&#946;1 &#40;GPIa-IIa&#41; is associated with high expression of the receptor and may lead to platelet hyperreactivity&#44; even though this polymorphism does not alter the amino acid sequence of the protein&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">14&#44;15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">At least nine polymorphisms have been described in the beta3 subunit of integrin &#945;2b&#946;3&#46; Incompatibility for HPA-1 &#40;PlA&#41; alloantigens is the most common cause of fetal and neonatal alloimune thrombocytopenia in Caucasians&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">16</span></a> The rs5918 polymorphism is a T&#62;C transition creating a missense Leu59Pro variant&#46; Studies on the functional consequences of this polymorphism in thrombotic diseases have yielded conflicting results&#44;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">17&#44;18</span></a> but an increase in platelet reactivity has been reported in C allele carriers &#40;PlA2&#41; compared with TT genotype individuals &#40;PlA1&#47;A1&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Various single nucleotide polymorphisms &#40;SNPs&#41; in intron regions of the <span class="elsevierStyleItalic">P2RY12</span> gene have been described&#44; some of them associated with greater ADP-induced platelet aggregation&#44; including rs2046934 &#40;C&#62;T&#41;&#44; rs6801273 &#40;T&#62;C&#41; and rs6798347 &#40;G&#62;A&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">20</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">As platelets play an important role in the pathophysiology of myocardial infarction &#40;MI&#41;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">21</span></a> and there is controversy regarding the possible association of platelet polymorphisms and increased cardiovascular risk&#44;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">22</span></a> further studies in specific populations are necessary to clarify the status of this relationship&#46; In this study&#44; we assessed the potential role of eight polymorphisms&#44; one VNTR and seven SNPs&#44; of four genes coding for platelet receptors &#40;<span class="elsevierStyleItalic">GP1BA</span>&#44; <span class="elsevierStyleItalic">ITGB3</span>&#44; <span class="elsevierStyleItalic">ITGA2</span> and <span class="elsevierStyleItalic">P2RY12</span>&#41; as risk factors for MI&#46; To this end&#44; two groups of patients were analyzed according to the age at which they suffered MI&#58; 45 years or younger &#40;MI &#8804;45&#41; and more than 45 years &#40;MI &#62;45&#41;&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Population</span><p id="par0060" class="elsevierStylePara elsevierViewall">The study population included only Portuguese Caucasians&#46; Subjects were divided into three groups&#58; controls&#44; MI &#8804;45 and MI &#62;45&#46; The control group consisted of 235 subjects &#40;57 male and 178 female&#41; with ages ranging from 15 to 69 years &#40;mean 27 years&#41;&#46; The characteristics of the control group have been described previously&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">23</span></a> except for polymorphisms of the ADP receptor gene <span class="elsevierStyleItalic">P2RY12</span>&#46; At the time of blood sample collection&#44; subjects had no clinical signs of hemorrhagic or thrombotic disease&#46; The MI &#8804;45 group consisted of 44 patients &#40;40 male and four female&#41; who had suffered an MI at or before the age of 45 years&#44; with ages ranging from 27 to 45 years &#40;mean 42 years&#41;&#46; The MI &#62;45 group consisted of 78 patients &#40;67 male and 11 female&#41; who had suffered an MI after the age of 45 years&#44; with ages ranging from 51 to 97 years &#40;mean 67 years&#41;&#46; Clinical data on smoking status&#44; blood pressure&#44; presence of diabetes&#44; body mass index&#44; family history of cardiovascular disorders and total cholesterol levels were collected for the three groups&#46; All subjects gave their written informed consent to the protocol&#44; which was approved by the local ethics committee&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Genotype analysis</span><p id="par0065" class="elsevierStylePara elsevierViewall">Genomic DNA was extracted from peripheral blood cells collected by venipuncture in EDTA tubes using a PureLink&#8482; Genomic DNA Mini Kit &#40;Invitrogen&#41;&#46; A region containing each polymorphism was amplified by polymerase chain reaction using 1 &#956;g of DNA and 1 &#956;M of specific primers &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Except for the VNTR polymorphism&#44; amplicons were then digested with specific restriction enzymes &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; and the digested fragments were visualized in a 2&#37; ethidium bromide agarose gel&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">Genotype and allelic frequencies for the control group were calculated and Hardy-Weinberg equilibrium was tested for the eight polymorphisms by means of a chi-square test using observed vs&#46; expected genotype frequencies&#46; Genotype frequencies in the MI &#62;45 and MI &#8804;45 groups were compared with the observed genotype frequencies obtained in the control group using a chi-square test&#46; For chi-square test p values &#8804;0&#46;05&#44; odds ratios &#40;OR&#41; with 95&#37; confidence intervals &#40;CI&#41; were calculated as estimates of the occurrence of MI as a function of the studied polymorphisms&#46; Binary logistic regression analysis was performed to determine the association between MI and the studied variables through calculation of ORs and their 95&#37; CIs&#46; Adjusted ORs were estimated for genetic and physiological profiles using multinomial logistic regression &#40;adjusted maximum-likelihood estimation&#41;&#46; The enter method was selected for entering independent variables into the analysis&#46; IBM SPSS for Windows&#44; version 24&#46;0&#44; was used for all statistical calculations&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> presents the clinical data of the three study groups&#44; and shows statistically significant differences for non-genetic variables&#46; There were significant differences in smoking status &#40;OR 5&#46;651&#59; 95&#37; CI&#58; 2&#46;2472-14&#46;2041&#59; p&#60;0&#46;001&#41;&#44; hypertension &#40;OR 16&#46;755&#59; 95&#37; CI&#58; 4&#46;521-62&#46;500&#59; p&#60;0&#46;001&#41;&#44; diabetes &#40;OR 60&#46;948&#59; 95&#37; CI&#58; 3&#46;644-1019&#46;274&#59; p&#61;0&#46;004&#41; and obesity &#40;OR 5&#46;6515&#59; 95&#37; CI&#58; 2&#46;2472-14&#46;2041&#59; p&#60;0&#46;001&#41; between the control and MI &#8804;45 groups&#46; Hypertension &#40;OR 58&#46;823&#59; 95&#37; CI&#58; 17&#46;544-200&#46;000&#59; p&#60;0&#46;001&#41;&#44; diabetes &#40;OR 80&#46;119&#59; 95&#37; CI&#58; 4&#46;812-1334&#46;049&#59; p&#61;0&#46;002&#41;&#44; obesity &#40;OR 3&#46;472&#59; 95&#37; CI&#58; 1&#46;013-11&#46;905&#59; p&#61;0&#46;048&#41;&#44; family history of thrombosis &#40;OR 8&#46;707&#59; 95&#37; CI&#58; 2&#46;657-28&#46;532&#59; p&#60;0&#46;001&#41; and elevated cholesterol &#40;OR 3&#46;891&#59; 95&#37; CI&#58; 1&#46;292-11&#46;765&#59; p&#60;0&#46;016&#41; were significantly different between the control and MI &#62;45 groups&#46; There was also significant heterogeneity in gender distribution in the MI groups&#44; with a larger proportion of males in both groups &#40;p&#60;0&#46;001 for both&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Genotypes were in Hardy-Weinberg equilibrium for all polymorphisms in the control group&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the genotype frequencies for the eight polymorphisms in the three study groups and the p values obtained when the MI groups were compared with the control group for each polymorphism&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> also shows the same comparison between groups but adding the homozygotic and heterozygotic genotypes for the allele considered of higher risk&#46; This association of genotypes was performed due to the low numbers of patients with some genotypes&#46; As can be seen&#44; the p values for the rs5918 polymorphism of integrin beta3 were not significant&#44; meaning that there were no statistical differences between the control and MI groups &#40;p&#61;0&#46;579 and p&#61;0&#46;359 for MI &#62;45 and p&#61;0&#46;407 and p&#61;0&#46;722 for MI &#8804;45&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">There was also no statistically significant difference between the control and MI groups for GPIb alpha polymorphisms&#46; The p value for the rs2243093 polymorphism was 0&#46;104 when MI &#8804;45 was compared with the control group&#46; It is important to note that for this polymorphism only one homozygote &#40;CC&#41; was found&#44; corresponding to one control individual&#46; For the rs6065 polymorphism&#44; as in the previous case&#44; although the prevalence of CT heterozygotes was higher in MI &#8804;45 &#40;26&#46;2&#37;&#41; compared with the control group &#40;18&#46;5&#37;&#41;&#44; the chi-square test was not statistically significant &#40;p&#61;0&#46;199&#41;&#46; No homozygotes &#40;TT&#41; were found for this polymorphism in all of the study population&#46; When the control group was divided into two subpopulations by age &#40;control &#8804;45 years and control &#62;45 years&#41; and only males were included&#44; rs6065 was the only polymorphism that showed a statistical difference&#58; p&#60;0&#46;001 for control &#8804;45&#44; males only &#40;n&#61;44&#41; compared with MI &#8804;45&#44; males only &#40;n&#61;38&#41;&#46; The phenotype distribution was 41 CC and 3 CT for control &#8804;45&#44; males only and 27 CC and 11 CT for MI &#8804;45&#44; males only&#46; When ORs were calculated for CT vs&#46; CC genotypes in MI &#8804;45&#44; males only&#44; the p value was 0&#46;016 &#40;OR 5&#46;568&#59; 95&#37; CI&#58; 1&#46;421-21&#46;822&#41;&#46; No adjusted ORs were calculated due to the low numbers in these subgroups &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">With respect to the other GPIb alpha polymorphism studied&#44; VNTR&#44; no differences were found in chi-square tests &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; In our study population&#44; no A allele for VNTR was found&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">For the integrin alpha2 polymorphism rs938043469&#44; a significant difference was found in the p value when the MI &#62;45 group was compared with the control group &#40;p&#61;0&#46;011&#41;&#46; This difference was mainly due to a greater proportion of TT homozygotes &#40;19&#46;2&#37; in MI &#62;45 vs&#46; 9&#46;9&#37; in controls&#41; and fewer CC homozygotes &#40;28&#46;2&#37; in MI &#62;45 vs&#46; 38&#46;7&#37; in controls&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Accordingly&#44; the OR for MI &#62;45 was significantly higher in TT vs&#46; CC genotypes &#40;OR 2&#46;662&#44; CI&#58; 1&#46;181-6&#46;001&#44; p&#61;0&#46;027&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; After adjustment&#44; the OR remained statistically significant&#44; meaning that patients with a TT genotype have a greater risk of MI after the age of 45 years independently of other variables &#40;OR 2&#46;852&#44; 95&#37; CI&#58; 1&#46;092-7&#46;451&#44; p&#61;0&#46;032&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; No differences were found between the control and MI &#8804;45 groups for this polymorphism&#46; When both patient groups were compared by means of binary logistic regression analysis&#44; patients with the TT genotype were more likely to suffer MI after the age of 45 years &#40;OR 4&#46;528&#44; 95&#37; CI&#58; 1&#46;047-19&#46;576&#44; p&#61;0&#46;043&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">For the three <span class="elsevierStyleItalic">P2RY12</span> polymorphisms studied&#44; there was a significant difference in rs2046934 when the MI &#62;45 and control groups were compared in terms of associated genotypes&#44; AG&#43;GG &#40;p&#61;0&#46;043&#41;&#46; This difference was due to a greater proportion of heterozygotes in the MI &#62;45 group compared with controls&#46; However&#44; when ORs were calculated comparing the AA and AG&#43;GG genotypes&#44; the difference was not statistically significant &#40;OR 1&#46;665&#44; CI&#58; 0&#46;933-2&#46;970&#44; p&#61;0&#46;090&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Discussion</span><p id="par0105" class="elsevierStylePara elsevierViewall">In this study&#44; we analyzed the effect of several platelet gene polymorphisms in patients who had suffered MI&#46; These patients were divided into two groups according to the age at which they suffered MI&#58; 45 years or younger and more than 45 years&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">According to our results&#44; the only polymorphism significantly associated with an increased risk for MI in the overall study population was rs938043469 in the alpha2 subunit &#40;GPIa&#41; of integrin &#945;2&#946;1&#46; We also concluded that the presence of the T allele in homozygosity is essential for this increased risk of MI&#46; Nevertheless&#44; the rs938043469 polymorphism does not appear to influence early onset of MI&#44; since the results for the MI &#8804;45 group showed no correlation between the presence of this polymorphism and MI &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The frequency of the TT genotype in the control group &#40;9&#46;9&#37;&#41; was within the range of previous reports&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">24&#8211;26</span></a> The proportion of the TT genotype in the MI &#62;45 group &#40;19&#46;2&#37;&#41; was higher than in the control group&#46; Since Kunicki et al&#46; first described this polymorphism in 1997&#44;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">27</span></a> several studies have assessed the relationship between the polymorphism and cardiovascular disease&#44; mainly in younger adults&#44; with conflicting results&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">25&#44;28</span></a> In 2007&#44; a meta-analysis of published data regarding the role of rs938043469 in coronary artery disease &#40;CAD&#41; concluded that there was no association between this polymorphism and CAD&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">29</span></a> Nevertheless&#44; our results were very similar to those of Jian-Xia Lu et al&#46; in Chinese patients who had suffered ischemic stroke&#44;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">24</span></a> despite the differences in ethnicity and cardiovascular diseases&#46; Moreover&#44; a recent meta-analysis found that the T allele or TT genotype of the rs938043469 polymorphism were associated with increased risk for ischemic stroke&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">30</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Although a silent polymorphism&#44; rs938043469 is believed to influence the density of integrin &#945;2&#946;1 &#40;GPIa-IIa&#41; in the platelet membrane&#44; with the T allele being responsible for the highest expression of the glycoprotein&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">14&#44;15</span></a> This variation in receptor density may account for greater platelet responsiveness to collagen in the TT genotype&#44; enhancing the thrombotic potential of platelets in pathological states&#46; However&#44; it should be remembered that this receptor&#44; despite its importance for platelet adhesion to subendothelial collagen&#44; particularly in static conditions&#44; is not physiologically as important as GPIb-V-IX for the initiation of adhesion to subendothelial tissue in conditions of high shear stress as found in the arterial circulation&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">31</span></a> This may explain the difficulty in finding statistically significant evidence for the role of this polymorphism in certain cardiovascular diseases&#46; The conflicting results found may also reflect different study designs&#44; patients and diseases<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">24&#8211;26&#44;28&#44;30</span></a> and the difficulty in establishing that a single polymorphism is in itself crucial to such a complex and multifactorial event as MI&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In many studies&#44; including the present one&#44; some results may fail to reach statistical significance&#44; and as a result it may be impossible to decide definitively whether a particular association exists&#46; Nevertheless&#44; in our opinion&#44; such results should not necessarily be disregarded&#44; but should be analyzed carefully in order to determine their biological significance&#46; Examples of such results are those concerning the rs2243093&#44; rs6065&#44; VNTR and rs2046934 polymorphisms in our MI groups&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Analysis of the rs2243093 polymorphism revealed a higher proportion of the TC genotype in the MI &#8804;45 group than in controls and the chi-square test was very close to significance &#40;p&#61;0&#46;104&#41;&#46; A similar result was found in two studies in which the rs2243093 polymorphism was associated with an increased risk of ischemic stroke&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">32&#44;33</span></a> In these studies&#44; a higher frequency of the TC genotype was reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">32&#44;33</span></a> Another study associating the rs2243093 polymorphism and risk of CAD published in 2015 by Zhang et al&#46; found a high frequency of the CC genotype and concluded that this genotype is a biomarker of genetic susceptibility&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">34</span></a> Interestingly&#44; there was only one individual with the CC genotype in our control group&#44; corresponding to a frequency of 0&#46;4&#37; in the overall population&#44; which is within the range of other populations&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">13</span></a> This polymorphism lies in the 5&#8242; UTR of the <span class="elsevierStyleItalic">GP1BA</span> gene&#44; where a T or a C may be present in position -5 from the ATG start codon&#46; The C allele has been associated with increased expression of the receptor on the cell membrane&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">13</span></a> which may explain the link between this polymorphism and greater likelihood of arterial thrombus formation in some vascular pathologies&#44; due to increased platelet adhesiveness&#46; Nevertheless&#44; our results did not show a clear correlation between the Kozak polymorphism and MI in any of the MI groups studied&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">In the rs6065 polymorphism&#44; threonine or methionine is found at position 161 of GPIb alpha due to a C1018T nucleotide change&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">35</span></a> rs6065 is of clinical importance because it is implicated in neonatal alloimmune thrombocytopenic purpura&#44; post-transfusion purpura&#44; and refractoriness to HLA-matched platelet transfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">36</span></a> The presence of methionine has been associated with increased risk for MI and CAD in several studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">34&#44;37</span></a> However&#44; in a study of the functional effects of this polymorphism in 2003&#44; Ulrichts et al&#46; described a stronger interaction between the GPIb alpha subunit and vWF in glycoproteins that carry threonine &#40;C allele&#41; than methionine &#40;T allele&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">38</span></a> This finding does not agree with the above results&#46; Nevertheless&#44; as the authors point out in their paper&#44; vWF binding to GPIb alpha was investigated in a stationary state and not in the shear stress conditions usually seen in a vascular stenosis&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">38</span></a> We found a higher percentage of CT heterozygotes in the MI &#8804;45 group than in the control group&#44; while in the MI &#62;45 group no differences were found from the control group&#46; These results&#44; although not statistically significant&#44; are in agreement with the findings of Mikkelsson et al&#46;&#44; who reported a correlation between the presence of Met161 and sudden cardiac death in men aged less than 55 years&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">37</span></a> Interestingly&#44; when we reanalyzed the statistics including only men in the control &#8804;45 and MI &#8804;45 groups&#44; there was a significant difference &#40;p&#60;0&#46;001&#41; in genotype distribution&#44; with a higher percentage of heterozygotes in MI &#8804;45 compared with control &#8804;45&#46; This result&#44; despite the low numbers involved&#44; especially in control &#8804;45&#44; highlights the possible contribution of the rs6065 polymorphism to early MI&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">For the VNTR polymorphism in GPIb alpha&#44; no A allele &#40;four repeats&#41; and one rare E allele&#44; which has only been reported in Caucasians&#44; were found in our study groups&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">39</span></a> The A allele has been reported mainly in Japanese and Native American populations&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">40</span></a> The most interesting result that we observed regarding this polymorphism was the higher frequency of the BC genotype in MI &#8804;45 than in the control and MI &#62;45 groups&#46; However&#44; the p value was not significant&#46; This may be due to the large number of classes &#40;six genotypes&#41; and the small sample size&#44; especially in the MI &#8804;45 group&#46; The literature often attributes a protective role to the CC genotype&#44;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">41</span></a> and it should be noted that that the CC genotype was more frequent in the control group than in the MI &#62;45 and MI &#8804;45 groups&#46; Studies assessing the physiological response of each of the different sized GPIb alpha subunits are needed&#46; In one attempt to help clarify this issue we conducted a study in which platelets with different VNTR genotypes were subjected to PFA-100&#174; testing using collagen&#47;ADP and collagen&#47;epinephrine cartridges and occlusion time was measured&#46; Our preliminary results showed that platelets with the CC genotype take longer to occlude the cartridge than platelets bearing a B allele &#40;BC or BD&#41;&#44; supporting its previously reported protective role &#40;data not shown&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The p value for the rs2046934 polymorphism was statistically significant&#46; This difference was found when AG and GG genotypes were associated and&#44; as in the C807T polymorphism&#44; the difference was seen in the MI &#62;45 group&#46; When associated&#44; the difference was due to a greater number of heterozygotes in the MI &#62;45 than in the control group&#46; rs2046934 is an intronic polymorphism that does not alter the amino acid sequence of the protein and is in linkage disequilibrium with other polymorphisms that also do not change the protein structure of the receptor&#46; All these polymorphisms form the H2 haplotype of the <span class="elsevierStyleItalic">P2RY12</span> gene&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">20</span></a> In aggregometry tests&#44; the H2 haplotype was associated with higher maximal aggregation in response to ADP than the H1 haplotype&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">20</span></a> This result suggests a possible relationship between the H2 haplotype and atherothrombosis&#46; However&#44; a study by Amisten et al&#46; found no association between the H2 haplotype and MI&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">42</span></a> In the present study&#44; although there were differences in the chi-square test result&#44; the p value of an odds ratio test calculated for AG&#43;GG vs&#46; AA genotypes in the MI &#62;45 group was not statistically significant&#46; In a recent study assessing the effects of platelet polymorphisms on antiplatelet drug responsiveness and clinical outcomes in patients with acute minor ischemic stroke that included the <span class="elsevierStyleItalic">P2RY12</span> gene&#44; the authors did not find that any of the P2RY<span class="elsevierStyleInf">12</span> polymorphisms that we also studied had a pathophysiological effect&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">43</span></a> Additional studies should be conducted to elucidate the pathophysiological role&#44; if any&#44; of the rs2046934 polymorphism&#46; For the other P2RY<span class="elsevierStyleInf">12</span> polymorphisms studied no statistical differences were found&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The rs5918 polymorphism showed no correlation or trend with MI in any MI group&#46; Although several studies have suggested an association between PlA2 &#40;the C allele&#41; and arterial events&#44;<a class="elsevierStyleCrossRefs" href="#bib0455"><span class="elsevierStyleSup">44&#44;45</span></a> we found no statistical correlation between this polymorphism and MI&#44; as also reported in several other studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">46&#44;47</span></a> and controversy remains concerning the relationship between this polymorphism and cardiovascular pathology&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The results of the present work&#44; despite its inherent limitations&#44; particularly a limited number of patients in our MI groups and the heterogeneity between controls and MI patient groups&#44; provide important hints on the possible role of platelet receptor polymorphisms in thrombotic disease&#46; The most important conclusion of our work is that the TT genotype of the rs938043469 polymorphism of integrin alpha2 &#40;GPIa&#41; is significantly associated with the presence of MI in patients older than 45 years&#46; Further studies with larger and more homogenous cohorts may support our findings and help to clarify the role of the rs6065 and rs2046934 polymorphisms and their association with MI&#46; It is important to point out that the two groups of MI patients also differ in non-genetic variables&#44; and so further studies are required to understand the molecular pathways associated with the polymorphisms under study&#46; In addition&#44; the association between these polymorphisms and clinical outcomes should be studied to enable better stratification of MI patients according to their genetic profile&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            0 => "Myocardial infarction and platelet polymorphisms"
            1 => "GPIb-V-IX"
            2 => "GPIa-IIa"
            3 => "GPIIb-IIIa&#58; ADP P2Y12 receptor"
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            1 => "GP Ib-V-IX"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">We examined the potential role of polymorphisms of the platelet genes <span class="elsevierStyleItalic">GP1BA</span> &#40;rs2243093&#44; rs6065 and VNTR&#41;&#44; <span class="elsevierStyleItalic">ITGB3</span> &#40;rs5918&#41;&#44; <span class="elsevierStyleItalic">ITGA2</span> &#40;rs938043469&#41; and <span class="elsevierStyleItalic">P2RY12</span> &#40;rs2046934&#44; rs6801273 and rs6798347&#41; as risk factors for myocardial infarction &#40;MI&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The study population was divided into three groups&#58; controls &#40;n&#61;235&#41;&#44; MI at age &#8804;45 years &#40;MI &#8804;45&#44; n&#61;44&#41;&#44; and MI at age &#62;45 years &#40;MI &#62;45&#44; n&#61;78&#41;&#46; The control group was further divided into two subgroups &#40;control &#8804;45 and &#62;45&#41;&#44; and subgroups including only men were also considered for statistical analysis&#46; Polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism analysis&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Regarding non-genetic risk factors&#44; the control group differed statistically from the MI &#8804;45 group &#40;p&#60;00&#46;5&#41; in terms of smoking&#44; hypertension&#44; diabetes and obesity&#44; and from the MI &#62;45 group &#40;p&#60;0&#46;05&#41; in terms of hypertension&#44; diabetes&#44; obesity&#44; family history of thrombosis and high cholesterol&#46; For the studied <span class="elsevierStyleItalic">ITGA2</span> polymorphism&#44; a statistical difference was found when MI &#62;45 was compared with the control group&#44; with a higher risk of MI in the TT genotype &#40;OR 2&#46;852&#59; 95&#37; CI&#58; 1&#46;092-7&#46;451&#59; p&#61;0&#46;032&#41;&#46; In the <span class="elsevierStyleItalic">GP1BA</span> rs6065 polymorphism&#44; a statistically significant difference was found between control &#8804;45 only men and MI &#8804;45 only men&#44; with a higher risk in the CT genotype &#40;OR 5&#46;568&#59; 95&#37; CI&#58; 1&#46;421-21&#46;822&#59; p&#61;0&#46;016&#41;&#44; despite the low numbers included&#46; The other polymorphisms studied did not show any statistically significant correlations&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">There is a statistically significant association between the TT genotype of the <span class="elsevierStyleItalic">ITGA2</span> rs938043469 polymorphism and increased risk for MI &#62;45&#46;</p></span>"
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            "titulo" => "Introduction"
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            "titulo" => "Methods"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introdu&#231;&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Determinou-se o papel de polimorfismos dos genes de express&#227;o plaquet&#225;ria GP1BA &#40;rs2243093&#44; rs6065 e o VNTR p&#46;Ser415&#95;Thr428&#40;0&#95;4&#41;&#41;&#44; ITGB3 &#40;rs5918&#41;&#44; ITGA2 &#40;rs938043469&#41; e P2RY12 &#40;rs2046934&#44; rs6801273 e rs6798347&#41; como fatores de risco para o enfarte agudo do mioc&#225;rdio &#40;EAM&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A amostra foi dividida em tr&#234;s grupos&#58; Controlo &#40;n&#61;235&#41;&#44; EAM &#8804;45 anos &#40;n&#61;44&#41; e EAM &#62;45 anos &#40;n&#61;78&#41;&#46; O grupo Controlo foi ainda dividido em dois subgrupos &#40;Controlo &#8804;45 e &#62;45&#41;&#46; Subgrupos incluindo somente homens tamb&#233;m foram considerados para fins estat&#237;sticos&#46; Os polimorfismos foram estudados atrav&#233;s de PCR e RFLP&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Em rela&#231;&#227;o aos fatores de risco n&#227;o gen&#233;ticos&#44; o grupo Controlo diferia estatisticamente do grupo EAM &#8804; 45 anos &#40;p&#60;0&#44;05&#41; em termos de h&#225;bitos tab&#225;gicos&#44; hipertens&#227;o&#44; diabetes e obesidade e tamb&#233;m diferia do grupo EAM &#62;45 anos &#40;p&#60;0&#44;05&#41; nas vari&#225;veis hipertens&#227;o&#44; diabetes&#44; obesidade&#44; antecedentes familiares de trombose e colesterol&#46; Para o polimorfismo estudado do gene ITGA2&#44; verificou-se uma diferen&#231;a estatisticamente significativa quando se compararam os grupos EAM &#62;45 anos e Controlo&#44; associando-se o gen&#243;tipo TT a aumento de risco de EAM &#40;OR 2&#44;852&#59; IC 95&#37; de 1&#44;092 a 7&#44;451&#59; p&#61;0&#44;032&#41;&#46; No polimorfismo rs6065 do gene GP1BA foi encontrada uma diferen&#231;a estat&#237;stica quando comparados os grupos Controlo &#8804; 45 s&#243; homens e EAM &#8804; 45 s&#243; homens&#44; associando-se o gen&#243;tipo C&#47;T a um maior risco de EAM &#40;OR 5&#44;568&#59; IC 95&#37; de 1&#44;421 a 21&#44;822&#59; p&#61;0&#44;016&#41;&#44; apesar do baixo n&#46; Os outros polimorfismos n&#227;o apresentaram correla&#231;&#227;o significativa&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Existe uma associa&#231;&#227;o estat&#237;stica significativa entre o gen&#243;tipo T&#47;T do polimorfismo rs938043469 do gene ITGA2 e o risco de EAM &#62;45&#46;</p></span>"
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                  \t\t\t\t">F-CTACCGGCCCATGTCTAAATR-TCTTTGTCTTTTCCTTACTTTTTCA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Controls &#40;n&#61;235&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">40 &#40;90&#46;9&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">62 &#40;26&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">30 &#40;68&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">27 &#40;34&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Hypertension&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">16 &#40;36&#46;4&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">54 &#40;69&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Diabetes&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">10 &#40;22&#46;7&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">22 &#40;28&#46;2&#41;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Obesity &#40;BMI &#62;30 kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#44; n &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">8 &#40;3&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2018.03.017

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Year/Month	Html	Pdf	Total

2024 November	5	4	9
2024 October	26	28	54
2024 September	30	23	53
2024 August	25	19	44
2024 July	23	27	50
2024 June	25	19	44
2024 May	27	19	46
2024 April	21	20	41
2024 March	30	19	49
2024 February	29	31	60
2024 January	21	33	54
2023 December	14	28	42
2023 November	22	21	43
2023 October	16	11	27
2023 September	54	22	76
2023 August	56	17	73
2023 July	37	10	47
2023 June	19	16	35
2023 May	33	30	63
2023 April	16	6	22
2023 March	15	15	30
2023 February	17	17	34
2023 January	17	12	29
2022 December	22	14	36
2022 November	23	27	50
2022 October	17	19	36
2022 September	23	27	50
2022 August	40	31	71
2022 July	69	32	101
2022 June	27	17	44
2022 May	22	32	54
2022 April	22	25	47
2022 March	24	33	57
2022 February	18	32	50
2022 January	11	19	30
2021 December	18	28	46
2021 November	25	28	53
2021 October	29	39	68
2021 September	19	22	41
2021 August	20	27	47
2021 July	14	17	31
2021 June	21	16	37
2021 May	31	38	69
2021 April	27	51	78
2021 March	24	19	43
2021 February	22	16	38
2021 January	24	13	37
2020 December	21	11	32
2020 November	11	11	22
2020 October	12	15	27
2020 September	15	9	24
2020 August	8	8	16
2020 July	21	6	27
2020 June	16	14	30
2020 May	20	5	25
2020 April	16	12	28
2020 March	31	3	34
2020 February	60	14	74
2020 January	52	6	58
2019 December	23	1	24
2019 November	30	8	38
2019 October	47	6	53
2019 September	11	6	17
2019 August	10	7	17
2019 July	10	13	23
2019 June	18	19	37
2019 May	19	15	34
2019 April	22	13	35
2019 March	10	17	27
2019 February	11	5	16
2019 January	5	6	11
2018 December	7	15	22
2018 November	15	18	33
2018 October	59	33	92

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