Sortilin and the risk of cardiovascular disease | Revista Portuguesa de Cardiologia (English edition)

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"identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Sortilina e risco de doença cardiovascular" ] ] "textoCompleto" => "IntroductionCardiovascular disease is the leading cause of death in developed countries,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> and is responsible for 32% of deaths recorded in Portugal, according to the National Institute of Statistics.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Coronary artery disease (CAD), in particular, represents a major clinical problem, accounting for one in five deaths in the US.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> Multiple factors contribute to the development of CAD but it is well established that one of its key determinants is plasma LDL-C level. According to estimates by the WHO, about 9 million deaths/year and more than 75 million years of life lost/year are due to hypertension or hypercholesterolemia.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Overall, hypercholesterolemia is responsible for 18% of recorded events of cerebrovascular disease (CVD), mostly non-fatal events, and 56% of ischemic heart disease.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The data for Europe suggest that hypercholesterolemia may be responsible for up to 12% of disability-adjusted life years.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> Given the size of these numbers, many attempts have been made to elucidate the pathways that regulate LDL metabolism. It is now known that, for small groups of individuals, high cholesterol levels may be of genetic origin. There is even a Mendelian disease associated with high blood cholesterol: familial hypercholesterolemia.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Most patients suffering from this condition present pathogenic mutations in the gene that codes for the LDL receptor (LDLR), but it has been reported that defects in the apolipoprotein (apo) B gene (APOB), or less commonly, in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, may also be associated with this clinical phenotype.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> Mutations in any of these genes lead to either loss (LDLR and APOB) or gain (PCSK9) of function of its associated protein and high cardiovascular risk.However, there are few cases in which it is possible to relate a specific gene mutation to CVD. The pathogenesis of the major forms of CVD involves behavioral, environmental and genetic factors and the genetic component is known to be highly complex, resulting from the interaction of multiple genetic determinants.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> There are, however, several polymorphisms in these and other genes involved in lipid metabolism that, even though presenting a smaller effect on the protein for which they code, may play a significant part in CVD risk (reviewed in <a class="elsevierStyleCrossRef" href="#bib0030">6</a>).With the advent of new sequencing technologies, the search for a deeper understanding of these mechanisms, as well as the genetic basis of other risk factors, has gained new impetus; it has become possible to screen large populations for the genetic basis for complex diseases. Ultimately, such epidemiological studies may lead to a better understanding of etiological pathways and contribute to the development of new strategies for prevention and treatment.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Recently, large-scale genome-wide association studies (GWAS) have made it possible to identify a novel set of DNA variants that influence plasma LDL-C levels. The most consistent of these associations was observed in a cluster of genes on chromosome 1p13. The clinical relevance of this novel pathway is highlighted by the 40% difference in risk of myocardial infarction (MI) between individuals homozygous for the minor (less common) and major (more common) alleles of the p13 locus on chromosome 1. The effect is comparable to that attributed to common variants of LDLR and PCSK9 and greater than that described for the most common variants in HMGCR (the gene that codes for 3-hydroxy-3-methylglutaryl-coenzyme A reductase,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> the therapeutic target of statins, which is the class of drugs most commonly used in the treatment of hyperlipidemias). The SORT1 gene is located in the 1p13 cluster. This gene codes for sortilin, a multifunctional protein whose biological importance is becoming clearer as it is revealed to have novel and unexpected functions. Although its functions as a receptor for various ligands were already known, given the clear association reported by different GWAS, three independent teams<a class="elsevierStyleCrossRefs" href="#bib0050">10–12</a> set out to elucidate the biological mechanism relating sortilin to LDL-C levels and, ultimately, to risk of CAD. To this end, they used different mechanistic approaches and, interestingly, came to different conclusions. Here we summarize each of these approaches and their main conclusions, and attempt to reconcile the apparently discrepant results.Looking for a needle in a haystack: genome-wide association studiesOver the past few years, with the emergence and spread of third-generation sequencers, advances in sequencing and genotyping have catapulted GWAS to the forefront of population studies, with special focus on the relationship between genotype and common diseases. These studies are based on the premise that, for a large number of such diseases, the underlying hereditary variations have a minor allele frequency of more than 5%. It is then possible, through the analysis of large population samples, to identify associations of certain diseases with certain regions of the genome, both coding and non-coding. In fact, several genetic variants identified through GWAS are located in non-coding regions of the genome. Interpretation of the effects of the identified variants depends largely on the knowledge available on those regions. The possibility of genes located in the target region being responsible for the detected association is then estimated, without excluding the possibility that it may result from long-range genetic interactions or from other unknown reasons. The challenge is to understand the biological basis of the signs revealed in GWAS. Although this may be difficult, GWAS have already uncovered important genetic factors underlying a number of complex diseases. One of the most successful cases in terms of identification of single-nucleotide polymorphisms (SNPs) which are relevant to the pathogenesis of a complex disease is in fact the annotation of genes correlated with plasma lipid and lipoprotein levels, factors which have long been known to be important in pathological conditions such as dyslipidemia and MI. Over the last few years more than 100 loci have been described as associated with genetic variation in triglyceride, LDL-C and high-density lipoprotein (HDL) cholesterol levels.<a class="elsevierStyleCrossRefs" href="#bib0065">13–20</a> In the cases of CAD and MI, GWAS identified a smaller number of genetic loci, some of which were also associated with changes in traditional risk factors. A comprehensive analysis of several GWAS has identified and annotated CAD-associated loci,<a class="elsevierStyleCrossRefs" href="#bib0070">14,17,21–23</a> by combining data from the Welcome Trust Case Control Consortium and the German MI Family Study. It presented evidence of associations between seven chromosomal loci and CAD risk<a class="elsevierStyleCrossRef" href="#bib0070">14</a>: 1p13 (SARS, CELSR2, PSRC1, MYBPHL, SORT1, PSMA5 and SYPL2), 1q41 (MIA3), 2q36 (intergenic region), 6q25.1 (MTHFD1L), 9p21 (CDKN2A and CDKN2B), 10q11 (intergenic region) and 15q22.33 (SMAD3). The immediate question that arose was whether these new loci affected already known cardiovascular risk factors. To clarify this question, Samani et al.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> investigated the association of these seven loci with a number of quantitative traits of known relevance to cardiovascular disease, and showed that only the risk locus on chromosome 1p13 was significantly associated with higher LDL-C levels. The strongest association was located in the intergenic region including the PSRC1 and CELSR2 genes, which code for proline/serine-rich coiled-coil 1 and cadherin EGF, respectively. The function of these proteins remains unknown, but their coding genes are located close to the gene that codes for sortilin, SORT1. None of these three genes, nor any of the others present in the 1p13 locus, have ever been associated with a known Mendelian disease affecting LDL-C levels.<a class="elsevierStyleCrossRefs" href="#bib0050">10,13,20</a>Usual and unusual suspects: low-density lipoprotein cholesterol and sortilinGiven such a statistically significant association between the 1p13 locus and plasma LDL-C levels, the search for its explanatory mechanism became the research focus of various teams.Firstly, it was important to clarify which particular genomic variant was causing this association. Due to the linkage disequilibrium (extensive and non-random relationship) between multiple SNPs at the 1p13 locus (comprising the genes SORT1, PSRC1 and CELSR2), it was impossible to identify the causal variant solely through GWAS. In silico, in vitro and in vivo studies would be required to clarify this point, as well as the mechanisms behind this association. As these studies were being carried out, one gene began to stand out from all the others comprising this CAD risk locus: the SORT1 gene, which codes for sortilin.<a class="elsevierStyleCrossRefs" href="#bib0050">10–12</a>Sortilin belongs to the Vps10p domain receptor family, which consists of five known members. It is synthesized as a propeptide, cleaved in the Golgi apparatus by proprotein convertases, after which the protein takes its mature form, which allows proper ligand binding. Functionally, sortilin is a receptor of multiple ligands, including lipoprotein lipase (LPL),<a class="elsevierStyleCrossRef" href="#bib0120">24</a> the A-V apolipoproteins (apo A-V),<a class="elsevierStyleCrossRef" href="#bib0125">25</a> neurotensin<a class="elsevierStyleCrossRef" href="#bib0130">26</a> and receptor-associated protein (RAP).<a class="elsevierStyleCrossRef" href="#bib0135">27</a> It is also responsible for mediating Golgi-to-lysosome transport of a number of lysosomal proteins, some (but not all) enzymatic: sphingolipid activator proteins (SAPs): prosaposin and GM2 activator protein (GM2AP), acid sphingomyelinase, cathepsin H and cathepsin D.<a class="elsevierStyleCrossRefs" href="#bib0120">24,28–30</a> In recent years, it has been demonstrated that sortilin is involved in a number of important biological processes such as the formation of glucose transport 4 (GLUT-4) storage vesicles in response to insulin during adipocyte differentiation.<a class="elsevierStyleCrossRef" href="#bib0155">31</a> In the brain, it is part of a signaling complex that regulates cell survival.<a class="elsevierStyleCrossRef" href="#bib0160">32</a>The importance of these multiple properties in vivo remains unclear but it is evident that sortilin is a protein with an important biological role, deregulation of which is likely to cause severe side-effects that may go beyond its effect on plasma LDL-C levels.An exemplary approach: mechanistic analysesIn 2010, three independent teams published results from pioneering studies which set out to clarify the biological mechanism underlying the association between the 1p13 locus and plasma LDL levels.<a class="elsevierStyleCrossRefs" href="#bib0050">10–12</a> Based on solid, though different, experimental approaches, all three studies indicate that the SORT1 gene is responsible for the increased risk of CAD and/or MI. Curiously, the studies reached conclusions that were not only different but, in some cases, even opposite concerning the role of sortilin in the secretion of very low-density lipoprotein cholesterol (VLDL-C) (reviewed in <a class="elsevierStyleCrossRefs" href="#bib0165">33,34</a>).The first in vitro evidence of the interaction between sortilin and LDL particles was presented by Linsel-Nitschke et al.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Through fine mapping of the 1p13 locus, the authors began by seeking the variant with the strongest signs of that association and identified the SNP rs599839, showing that the G allele was the one associated with reduced plasma LDL-C levels and lower cardiovascular disease risk. They demonstrated that individuals homozygous for the G allele showed increased expression of the SORT1, CELSR2 and PSRC1 genes in peripheral white blood cells. The strongest and most consistent association, however, was seen for SORT1 mRNA levels. These results were confirmed in human embryonic kidney cells (HEK293) over-expressing SORT1 that showed increased internalization of LDL-C particles, leading to lower LDL-C plasma levels.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>In the same year (2010), Musunuru et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> presented a multifaceted approach, a tour de force for the follow-up of GWAS.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Based on the previous recognition that the rs646776, rs599839, rs12740374 and rs629301 SNPs from the 1p13 locus were most strongly associated with plasma LDL-C levels and on the assumption that non-coding DNA variants may alter gene expression, Musunuru et al. started by analyzing the effects of these four variants on the mRNA levels of the six genes located in that locus: SARS, CELSR2, PSRC1, MYBPHL, SYP2 and SORT1. They found that in human liver the minor allele for the rs646776 SNP was associated with increased expression of the SORT1, CELSR2 and PSRC1 genes,<a class="elsevierStyleCrossRef" href="#bib0180">36</a> with the strongest association observed for SORT1 mRNA levels and its corresponding protein, sortilin. Fine mapping of the region of interest led to the identification of the haplotypes defined by the SNPs present in 6.1 kilobases located between the CELSR2 and PSRC1 genes, and to the identification of the SNP rs12740374 as the one ultimately responsible for the association observed in GWAS. Bioinformatic analysis showed that, altering the wild-type sequence from GGTGCTCAAT to GTTGCTCAAT, the minor allele of this variant created a binding site for the CCAAT/enhancer binding protein (C/EBP) α, increasing promoter activity and SORT1 expression level. This was later confirmed in vitro. It should be noted that these results are in full agreement with the findings of Linsel-Nitsche's group<a class="elsevierStyleCrossRef" href="#bib0055">11</a> concerning mRNA expression levels in the liver. Finally, through studies on liver cells from mutant mice in which the gene coding for sortilin was over-expressed or inactivated, Musunuru et al. demonstrated that sortilin expression levels modulate the hepatic secretion of VLDL. The transgenic mouse chosen by this team was Apobec1−/−, a humanized mouse in which the gene that encodes the C->U-editing enzyme APOBEC-1 is suppressed, with a lipid profile closer to that seen in humans, in whom LDL is the predominant cholesterol transporter in circulation, rather than that typical of mice. When Musunuru et al. over-expressed the SORT1 gene in Apobec1−/− liver cells, a 70% reduction in plasma total cholesterol (TC) and LDL-C was observed. Similarly, inactivation of SORT1 by short-interfering RNA (siRNA) led to increases of 46% in TC and 125% in LDL.In general, the data presented by these two teams support the findings of GWAS findings and reinforce the idea of a negative correlation between SORT1 mRNA levels and plasma LDL-C concentrations. However, in the same year a third mechanistic study addressing this association was published and in this case, the results were not so easily reconciled either with the results from the previous studies or with the previous assumptions inferred through GWAS.The results presented by Kjolby et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> were published almost simultaneously. These authors used as a model a double knockout mouse, Sort1−/−,Ldlr−/−, having observed that its hepatocytes presented reductions of 30% in TC levels, ∼50% in proteins containing apo B100 (VLDL and LDL), and ∼60% in atherosclerotic plaque area compared to Ldlr−/− single knockout mice. Next, they performed liver-specific SORT1 over-expression. Briefly, they found that sortilin deficiency led to a 50% reduction in the secretion of lipoproteins, whereas over-expression resulted in a 50% increase. Together, these results indicate a positive correlation between SORT1 expression and LDL-C levels, opposite to that observed by Musunuru et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Spot the differences: analysis of the resultsThe question of the discrepancy between the results of these three studies has been discussed by various experts, particularly Dubé<a class="elsevierStyleCrossRef" href="#bib0170">34</a> and Tall and Ai,<a class="elsevierStyleCrossRef" href="#bib0165">33</a> in 2011. These authors drew attention to the methodological differences between the studies of Linsel-Nitschke et al.,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> Musunuru et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> and Kjolby et al.,<a class="elsevierStyleCrossRef" href="#bib0060">12</a> and the effects that those differences may have had on their results. The three teams that set out to clarify the mechanism by which the 1p13 locus affects LDL levels and the risk of CAD opted for different experimental models, which appear to have influenced the final results. This implies that their conclusions, even though they are consistent and resulted from well-designed and consistent experiments, may not be comparable.The first important point is the metabolic background in which each of the experiments was carried out. Linsel-Nitschke and colleagues<a class="elsevierStyleCrossRef" href="#bib0055">11</a> conducted their investigation only in humans, unlike Musunuru et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> and Kjolby et al.,<a class="elsevierStyleCrossRef" href="#bib0060">12</a> who analyzed non-human animal models. Nevertheless, the latter teams chose mouse models with different metabolic profiles: Musunuru et al. worked with liver cells from a humanized mouse, Apobec−/−, while Kjolby et al. studied a sortilin and LDL receptor double knockout (Sort1−/−,Ldlr−/−). Musunuru's mouse produced and secreted abnormally high amounts of lipoproteins, mimicking the human lipid profile, which may have artificially modified sortilin's secretory pathways and availability. Kjolby's mouse had deficient lipoprotein catabolism, created by the repression of SORT1 expression within hepatocytes and a high-fat “western” diet. Finally, there are differences in gene regulation between the two species, man and mouse, as demonstrated by the absence of the C/EBPα binding site in mice.<a class="elsevierStyleCrossRefs" href="#bib0050">10,37</a> This may hinder extrapolation of mouse studies to humans with regard to sortilin.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>It should be noted that, taken together, in vivo observations from studies in mouse models show that sortilin assumes complementary liver functions, depending on the metabolic milieu in which it operates, and ultimately regulates VLDL secretion. The different results reviewed here seem to suggest that sortilin regulates VLDL secretion and traffic to the lysosome when intracellular apo B-100 levels are extremely high. Conversely, at low apo B-100 expression levels, sortilin regulates the formation and secretion of VLDL.<a class="elsevierStyleCrossRefs" href="#bib0165">33,34</a>Nevertheless, this putative role of sortilin in the formation and secretion of VLDL is hard to reconcile with GWAS results indicating a specific association with LDL-C but not with triglycerides, which are the major components of VLDL particles.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Taken together, even though the findings of these studies are in some ways contradictory, they also provide strong evidence of the existence of a novel regulatory pathway for lipoprotein metabolism and show that modulating this pathway could alter cardiovascular disease risk in humans. Nevertheless, there is still a long way to go before the whole process and its modulators are clearly understood.ConclusionBy genotyping high-frequency alleles, GWAS are limited to identifying alleles which exert minimal, or even negligible, effects on the phenotype.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Furthermore, the most common alleles appear to explain only a small portion of the phenotype.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Thus, a significant proportion of the inheritance of complex phenotypes such as cardiovascular disease (CAD in particular) remains unknown, despite all the efforts in this area through numerous GWAS. This portion of heredity has been called “missing heritability” or the “dark matter” of heritability.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> The supporters of GWAS argue that increasing the size of the study samples and SNP density will enable detection of alleles with very small effect sizes, revealing the portion of inheritance which remains unknown.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Nevertheless, some authors support an alternative strategy based on whole-genome direct sequencing as a way of identifying rare alleles with large effects on the phenotype.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Crucial to this are recent advances in DNA sequencing technology, with the development of new platforms for third-generation sequencing that enable low-cost whole genome sequencing and identification of rare and/or new variants. It is believed that each genome has approximately 10 000 non-synonymous variants, among approximately 3.5 million SNPs. Given the size of these numbers, this kind of sequencing is expected to dominate genetic studies in coming years, a trend that can already be seen.<a class="elsevierStyleCrossRefs" href="#bib0205">41–45</a>It does, however, appear that the “dark matter” of heritability is the product of complex interactions between factors of different types: genetic, genomic and epigenetic.<a class="elsevierStyleCrossRefs" href="#bib0195">39,46</a> Similarly, the phenotype is also the result of nonlinear and stochastic interactions between different genetic and non-genetic factors.Nevertheless, the discovery and systematization of new genetic variants associated with a particular complex phenotype is important, particularly for the example reported here, in which these techniques have led to the discovery of a previously unknown molecular pathway.The three reports reviewed here are exemplary approaches to the need to move from a “blind” statistical association given by GWAS to a mechanistic explanation of how a particular genetic variation can modulate a particular phenotype. In this case, GWAS results pointed to a particular starting point, the 1p13 locus,<a class="elsevierStyleCrossRefs" href="#bib0070">14,21–23</a> which eventually caught the attention of three independent teams who relied on different experimental approaches to unveil the basis of the statistical association, all of which identified the SORT1 gene as the modulator of LDL-C levels and MI risk. But, while their results were in agreement concerning the relevance of SORT1's role in the regulation of lipoprotein metabolism, their interpretations of the effect of its expression on plasma LDL-C levels and its underlying mechanism differed.Linsel-Nitschke and colleagues<a class="elsevierStyleCrossRef" href="#bib0055">11</a> proposed, on the basis of their observations, that overexpression of sortilin increases the internalization of LDL, with a consequent decrease in plasma levels. Soon afterwards, through studies in human cohorts, hepatocytes and mice, Musunuru et al.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> reported an inverse relationship between sortilin expression and circulating LDL-C levels, and proposed an explanatory mechanism through transcriptional regulation (liver-specific) of the SORT1 gene by the transcription factor C/EBPα. By contrast, Kjolby et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> observed a direct relationship between SORT1 expression and circulating LDL concentrations, suggesting this could result from increased VLDL secretion.Several explanations have been put forward for the discrepancy between these results; the answer seems to depend on sortilin itself, which appears to be a multifaceted protein that can assume different functions depending on circumstances.To summarize, the studies reviewed here presented strong evidence that SORT1 is a regulator of plasma LDL-C levels, adding a significant role to the sortilin-coding gene that was unknown until recently. The cellular pathway relating sortilin to lipid metabolism is still controversial but it is surely an issue that will be further explored. A full understanding of this pathway will be crucial to assess whether sortilin is a potential target for therapeutic interventions for hypercholesterolemia or CAD (reviewed in <a class="elsevierStyleCrossRefs" href="#bib0165">33–35</a>).Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "xres298804" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec281828" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres298805" "titulo" => "Resumo" ] 3 => array:2 [ "identificador" => "xpalclavsec281829" "titulo" => "Palavras-chave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Looking for a needle in a haystack: genome-wide association studies" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Usual and unusual suspects: low-density lipoprotein cholesterol and sortilin" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "An exemplary approach: mechanistic analyses" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Spot the differences: analysis of the results" ] ] ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusion" ] 6 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-01-11" "fechaAceptado" => "2013-02-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec281828" "palabras" => array:6 [ 0 => "Genome-wide association studies" 1 => "Coronary artery disease" 2 => "Low-density lipoprotein cholesterol" 3 => "Sortilin" 4 => "Functional genetics" 5 => "Lipoprotein metabolism" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec281829" "palabras" => array:6 [ 0 => "Genome wide association studies" 1 => "Doença das artérias coronárias" 2 => "Colesterol lipoproteína de baixa densidade" 3 => "Sortilina" 4 => "Genómica funcional" 5 => "Metabolismo das lipoproteínas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Plasma low-density lipoprotein cholesterol (LDL-C) levels are a key determinant of the risk of cardiovascular disease, which is why many studies have attempted to elucidate the pathways that regulate its metabolism. Novel latest-generation sequencing techniques have identified a strong association between the 1p13 locus and the risk of cardiovascular disease caused by changes in plasma LDL-C levels. As expected for a complex phenotype, the effects of variation in this locus are only moderate. Even so, knowledge of the association is of major importance, since it has unveiled a new metabolic pathway regulating plasma cholesterol levels. Crucial to this discovery was the work of three independent teams seeking to clarify the biological basis of this association, who succeeded in proving that SORT1, encoding sortilin, was the gene in the 1p13 locus involved in LDL metabolism. SORT1 was the first gene identified as determining plasma LDL levels to be mechanistically evaluated and, although the three teams used different, though appropriate, experimental methods, their results were in some ways contradictory. Here we review all the experiments that led to the identification of the new pathway connecting sortilin with plasma LDL levels and risk of myocardial infarction. The regulatory mechanism underlying this association remains unclear, but its discovery has paved the way for considering previously unsuspected therapeutic targets and approaches." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "O nível plasmático de c-LDL constitui um determinante chave para o risco de doença cardiovascular, razão pela qual muitos estudos têm procurado elucidar as vias que regulam o seu metabolismo. As novas técnicas de sequenciação de última geração permitiram identificar um forte sinal de associação entre o locus 1p13 e o risco de doença cardiovascular causada por alteração dos níveis de LDL no plasma. Como seria de esperar para um fenótipo complexo, os efeitos da variação nesse locus são apenas moderados, ainda assim, o conhecimento da associação foi de grande importância uma vez que conduziu à descoberta de uma nova via metabólica reguladora dos níveis de colesterol no plasma. Para tal, foram fundamentais os trabalhos efetuados por três equipas independentes, que ao procurarem esclarecer as bases biológicas da associação em causa conseguiram provar que o gene SORT1, codificador da sortilina, era o gene do locus 1p13 implicado no metabolismo das LDL. SORT1 foi o primeiro dos genes identificados como determinantes dos níveis plasmáticos de LDL a ser alvo de avaliação mecanística e embora cada uma das equipas recorresse a metodologias experimentais diferentes, mas igualmente apropriadas face à questão em investigação, os resultados que obtiveram foram contraditórios em alguns aspetos. Neste trabalho, revemos o caminho percorrido até à descoberta da nova via que relaciona a sortilina com os níveis plasmáticos de LDL e com o risco de enfarte do miocárdio. Ainda por esclarecer permanece o mecanismo regulador dessa ligação, mas a sua descoberta sugere novos alvos terapêuticos até há bem pouco tempo desconhecidos." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Coutinho MF, Bourbon M, Prata MJ, et al. Sortilina e risco de doença cardiovascular. Rev Port Cardiol. 2013;32:793–799." ] ] "nomenclatura" => array:1 [ 0 => array:3 [ "identificador" => "nom0005" "titulo" => "List of abbreviations" "listaDefinicion" => array:1 [ 0 => array:1 [ "definicion" => array:18 [ 0 => array:2 [ "termino" => "apo" "descripcion" => "apolipoprotein" ] 1 => array:2 [ "termino" => "C/EBP" "descripcion" => "CCAAT/enhancer binding protein" ] 2 => array:2 [ "termino" => "CAD" "descripcion" => "coronary artery disease" ] 3 => array:2 [ "termino" => "CVD" "descripcion" => "cerebrovascular disease" ] 4 => array:2 [ "termino" => "GLUT4" "descripcion" => "glucose transporter 4" ] 5 => array:2 [ "termino" => "GM2AP" "descripcion" => "GM2 activator protein" ] 6 => array:2 [ "termino" => "GWAS" "descripcion" => "genome-wide association studies" ] 7 => array:2 [ "termino" => "HDL" "descripcion" => "high-density lipoprotein" ] 8 => array:2 [ "termino" => "LDL" "descripcion" => "low-density lipoprotein" ] 9 => array:2 [ "termino" => "LDL-C" "descripcion" => "low-density lipoprotein" ] 10 => array:2 [ "termino" => "LPL" "descripcion" => "lipoprotein lipase" ] 11 => array:2 [ "termino" => "MI" "descripcion" => "myocardial infarction" ] 12 => array:2 [ "termino" => "RAP" "descripcion" => "receptor-associated protein" ] 13 => array:2 [ "termino" => "SAP" "descripcion" => "sphingolipid activator protein" ] 14 => array:2 [ "termino" => "siRNA" "descripcion" => "short interfering RNA" ] 15 => array:2 [ "termino" => "SNP" "descripcion" => "single-nucleotide polymorphism" ] 16 => array:2 [ "termino" => "TC" "descripcion" => "total cholesterol" ] 17 => array:2 [ "termino" => "VLDL-C" "descripcion" => "very low-density lipoprotein cholesterol" ] ] ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:46 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The global burden of cardiovascular disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "C. 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Review article

Sortilin and the risk of cardiovascular disease

Sortilina e risco de doença cardiovascular

Maria Francisca Coutinhoa,b,c,

Corresponding author

francisca_coutinho@yahoo.com

Corresponding author.

, Mafalda Bourbond, Maria João Pratab,c, Sandra Alvesa

a Grupo de Investigação em Doenças Lisossomais de Sobrecarga, Unidade de I&D, Departamento de Genética Humana, INSA, Porto, Portugal

b IPATIMUP, Porto, Portugal

c Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal

d Grupo de Investigação Cardiovascular, Unidade de I&D, Departamento de Promoção da Saúde e Doenças Crónicas, INSA, Lisboa, Portugal

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According to estimates by the WHO&#44; about 9 million deaths&#47;year and more than 75 million years of life lost&#47;year are due to hypertension or hypercholesterolemia&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Overall&#44; hypercholesterolemia is responsible for 18&#37; of recorded events of cerebrovascular disease &#40;CVD&#41;&#44; mostly non-fatal events&#44; and 56&#37; of ischemic heart disease&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The data for Europe suggest that hypercholesterolemia may be responsible for up to 12&#37; of disability-adjusted life years&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Given the size of these numbers&#44; many attempts have been made to elucidate the pathways that regulate LDL metabolism&#46; It is now known that&#44; for small groups of individuals&#44; high cholesterol levels may be of genetic origin&#46; There is even a Mendelian disease associated with high blood cholesterol&#58; familial hypercholesterolemia&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Most patients suffering from this condition present pathogenic mutations in the gene that codes for the LDL receptor &#40;<span class="elsevierStyleItalic">LDLR</span>&#41;&#44; but it has been reported that defects in the apolipoprotein &#40;apo&#41; B gene &#40;<span class="elsevierStyleItalic">APOB</span>&#41;&#44; or less commonly&#44; in the proprotein convertase subtilisin&#47;kexin type 9 &#40;<span class="elsevierStyleItalic">PCSK9</span>&#41; gene&#44; may also be associated with this clinical phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> Mutations in any of these genes lead to either loss &#40;<span class="elsevierStyleItalic">LDLR</span> and <span class="elsevierStyleItalic">APOB</span>&#41; or gain &#40;<span class="elsevierStyleItalic">PCSK9</span>&#41; of function of its associated protein and high cardiovascular risk&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">However&#44; there are few cases in which it is possible to relate a specific gene mutation to CVD&#46; The pathogenesis of the major forms of CVD involves behavioral&#44; environmental and genetic factors and the genetic component is known to be highly complex&#44; resulting from the interaction of multiple genetic determinants&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> There are&#44; however&#44; several polymorphisms in these and other genes involved in lipid metabolism that&#44; even though presenting a smaller effect on the protein for which they code&#44; may play a significant part in CVD risk &#40;reviewed in <a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#41;&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">With the advent of new sequencing technologies&#44; the search for a deeper understanding of these mechanisms&#44; as well as the genetic basis of other risk factors&#44; has gained new impetus&#59; it has become possible to screen large populations for the genetic basis for complex diseases&#46; Ultimately&#44; such epidemiological studies may lead to a better understanding of etiological pathways and contribute to the development of new strategies for prevention and treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Recently&#44; large-scale genome-wide association studies &#40;GWAS&#41; have made it possible to identify a novel set of DNA variants that influence plasma LDL-C levels&#46; The most consistent of these associations was observed in a cluster of genes on chromosome 1p13&#46; The clinical relevance of this novel pathway is highlighted by the 40&#37; difference in risk of myocardial infarction &#40;MI&#41; between individuals homozygous for the minor &#40;less common&#41; and major &#40;more common&#41; alleles of the p13 locus on chromosome 1&#46; The effect is comparable to that attributed to common variants of <span class="elsevierStyleItalic">LDLR</span> and <span class="elsevierStyleItalic">PCSK9</span> and greater than that described for the most common variants in <span class="elsevierStyleItalic">HMGCR</span> &#40;the gene that codes for 3-hydroxy-3-methylglutaryl-coenzyme A reductase&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> the therapeutic target of statins&#44; which is the class of drugs most commonly used in the treatment of hyperlipidemias&#41;&#46; The <span class="elsevierStyleItalic">SORT1</span> gene is located in the 1p13 cluster&#46; This gene codes for sortilin&#44; a multifunctional protein whose biological importance is becoming clearer as it is revealed to have novel and unexpected functions&#46; Although its functions as a receptor for various ligands were already known&#44; given the clear association reported by different GWAS&#44; three independent teams<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;12</span></a> set out to elucidate the biological mechanism relating sortilin to LDL-C levels and&#44; ultimately&#44; to risk of CAD&#46; To this end&#44; they used different mechanistic approaches and&#44; interestingly&#44; came to different conclusions&#46; Here we summarize each of these approaches and their main conclusions&#44; and attempt to reconcile the apparently discrepant results&#46;</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Looking for a needle in a haystack&#58; genome-wide association studies</span><p id="par0115" class="elsevierStylePara elsevierViewall">Over the past few years&#44; with the emergence and spread of third-generation sequencers&#44; advances in sequencing and genotyping have catapulted GWAS to the forefront of population studies&#44; with special focus on the relationship between genotype and common diseases&#46; These studies are based on the premise that&#44; for a large number of such diseases&#44; the underlying hereditary variations have a minor allele frequency of more than 5&#37;&#46; It is then possible&#44; through the analysis of large population samples&#44; to identify associations of certain diseases with certain regions of the genome&#44; both coding and non-coding&#46; In fact&#44; several genetic variants identified through GWAS are located in non-coding regions of the genome&#46; Interpretation of the effects of the identified variants depends largely on the knowledge available on those regions&#46; The possibility of genes located in the target region being responsible for the detected association is then estimated&#44; without excluding the possibility that it may result from long-range genetic interactions or from other unknown reasons&#46; The challenge is to understand the biological basis of the signs revealed in GWAS&#46; Although this may be difficult&#44; GWAS have already uncovered important genetic factors underlying a number of complex diseases&#46; One of the most successful cases in terms of identification of single-nucleotide polymorphisms &#40;SNPs&#41; which are relevant to the pathogenesis of a complex disease is in fact the annotation of genes correlated with plasma lipid and lipoprotein levels&#44; factors which have long been known to be important in pathological conditions such as dyslipidemia and MI&#46; Over the last few years more than 100 loci have been described as associated with genetic variation in triglyceride&#44; LDL-C and high-density lipoprotein &#40;HDL&#41; cholesterol levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;20</span></a> In the cases of CAD and MI&#44; GWAS identified a smaller number of genetic loci&#44; some of which were also associated with changes in traditional risk factors&#46; A comprehensive analysis of several GWAS has identified and annotated CAD-associated loci&#44;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;17&#44;21&#8211;23</span></a> by combining data from the Welcome Trust Case Control Consortium and the German MI Family Study&#46; It presented evidence of associations between seven chromosomal loci and CAD risk<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>&#58; 1p13 &#40;<span class="elsevierStyleItalic">SARS</span>&#44; <span class="elsevierStyleItalic">CELSR2</span>&#44; <span class="elsevierStyleItalic">PSRC1</span>&#44; <span class="elsevierStyleItalic">MYBPHL</span>&#44; <span class="elsevierStyleItalic">SORT1</span>&#44; <span class="elsevierStyleItalic">PSMA5</span> and <span class="elsevierStyleItalic">SYPL2</span>&#41;&#44; 1q41 &#40;<span class="elsevierStyleItalic">MIA3</span>&#41;&#44; 2q36 &#40;intergenic region&#41;&#44; 6q25&#46;1 &#40;<span class="elsevierStyleItalic">MTHFD1L</span>&#41;&#44; 9p21 &#40;<span class="elsevierStyleItalic">CDKN2A</span> and <span class="elsevierStyleItalic">CDKN2B</span>&#41;&#44; 10q11 &#40;intergenic region&#41; and 15q22&#46;33 &#40;<span class="elsevierStyleItalic">SMAD3</span>&#41;&#46; The immediate question that arose was whether these new loci affected already known cardiovascular risk factors&#46; To clarify this question&#44; Samani et al&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> investigated the association of these seven loci with a number of quantitative traits of known relevance to cardiovascular disease&#44; and showed that only the risk locus on chromosome 1p13 was significantly associated with higher LDL-C levels&#46; The strongest association was located in the intergenic region including the <span class="elsevierStyleItalic">PSRC1</span> and <span class="elsevierStyleItalic">CELSR2</span> genes&#44; which code for proline&#47;serine-rich coiled-coil 1 and cadherin EGF&#44; respectively&#46; The function of these proteins remains unknown&#44; but their coding genes are located close to the gene that codes for sortilin&#44; <span class="elsevierStyleItalic">SORT1</span>&#46; None of these three genes&#44; nor any of the others present in the 1p13 locus&#44; have ever been associated with a known Mendelian disease affecting LDL-C levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;13&#44;20</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Usual and unusual suspects&#58; low-density lipoprotein cholesterol and sortilin</span><p id="par0120" class="elsevierStylePara elsevierViewall">Given such a statistically significant association between the 1p13 locus and plasma LDL-C levels&#44; the search for its explanatory mechanism became the research focus of various teams&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Firstly&#44; it was important to clarify which particular genomic variant was causing this association&#46; Due to the linkage disequilibrium &#40;extensive and non-random relationship&#41; between multiple SNPs at the 1p13 locus &#40;comprising the genes <span class="elsevierStyleItalic">SORT1</span>&#44; <span class="elsevierStyleItalic">PSRC1</span> and <span class="elsevierStyleItalic">CELSR2</span>&#41;&#44; it was impossible to identify the causal variant solely through GWAS&#46; In silico&#44; in vitro and in vivo studies would be required to clarify this point&#44; as well as the mechanisms behind this association&#46; As these studies were being carried out&#44; one gene began to stand out from all the others comprising this CAD risk locus&#58; the <span class="elsevierStyleItalic">SORT1</span> gene&#44; which codes for sortilin&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;12</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Sortilin belongs to the Vps10p domain receptor family&#44; which consists of five known members&#46; It is synthesized as a propeptide&#44; cleaved in the Golgi apparatus by proprotein convertases&#44; after which the protein takes its mature form&#44; which allows proper ligand binding&#46; Functionally&#44; sortilin is a receptor of multiple ligands&#44; including lipoprotein lipase &#40;LPL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> the A-V apolipoproteins &#40;apo A-V&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> neurotensin<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> and receptor-associated protein &#40;RAP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> It is also responsible for mediating Golgi-to-lysosome transport of a number of lysosomal proteins&#44; some &#40;but not all&#41; enzymatic&#58; sphingolipid activator proteins &#40;SAPs&#41;&#58; prosaposin and GM2 activator protein &#40;GM2AP&#41;&#44; acid sphingomyelinase&#44; cathepsin H and cathepsin D&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;28&#8211;30</span></a> In recent years&#44; it has been demonstrated that sortilin is involved in a number of important biological processes such as the formation of glucose transport 4 &#40;GLUT-4&#41; storage vesicles in response to insulin during adipocyte differentiation&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> In the brain&#44; it is part of a signaling complex that regulates cell survival&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The importance of these multiple properties in vivo remains unclear but it is evident that sortilin is a protein with an important biological role&#44; deregulation of which is likely to cause severe side-effects that may go beyond its effect on plasma LDL-C levels&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">An exemplary approach&#58; mechanistic analyses</span><p id="par0140" class="elsevierStylePara elsevierViewall">In 2010&#44; three independent teams published results from pioneering studies which set out to clarify the biological mechanism underlying the association between the 1p13 locus and plasma LDL levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;12</span></a> Based on solid&#44; though different&#44; experimental approaches&#44; all three studies indicate that the <span class="elsevierStyleItalic">SORT1</span> gene is responsible for the increased risk of CAD and&#47;or MI&#46; Curiously&#44; the studies reached conclusions that were not only different but&#44; in some cases&#44; even opposite concerning the role of sortilin in the secretion of very low-density lipoprotein cholesterol &#40;VLDL-C&#41; &#40;reviewed in <a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a>&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">The first in vitro evidence of the interaction between sortilin and LDL particles was presented by Linsel-Nitschke et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Through fine mapping of the 1p13 locus&#44; the authors began by seeking the variant with the strongest signs of that association and identified the SNP rs599839&#44; showing that the G allele was the one associated with reduced plasma LDL-C levels and lower cardiovascular disease risk&#46; They demonstrated that individuals homozygous for the G allele showed increased expression of the <span class="elsevierStyleItalic">SORT1</span>&#44; <span class="elsevierStyleItalic">CELSR2</span> and <span class="elsevierStyleItalic">PSRC1</span> genes in peripheral white blood cells&#46; The strongest and most consistent association&#44; however&#44; was seen for <span class="elsevierStyleItalic">SORT1</span> mRNA levels&#46; These results were confirmed in human embryonic kidney cells &#40;HEK293&#41; over-expressing <span class="elsevierStyleItalic">SORT1</span> that showed increased internalization of LDL-C particles&#44; leading to lower LDL-C plasma levels&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">In the same year &#40;2010&#41;&#44; Musunuru et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> presented a multifaceted approach&#44; a <span class="elsevierStyleItalic">tour de force</span> for the follow-up of GWAS&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Based on the previous recognition that the rs646776&#44; rs599839&#44; rs12740374 and rs629301 SNPs from the 1p13 locus were most strongly associated with plasma LDL-C levels and on the assumption that non-coding DNA variants may alter gene expression&#44; Musunuru et al&#46; started by analyzing the effects of these four variants on the mRNA levels of the six genes located in that locus&#58; <span class="elsevierStyleItalic">SARS</span>&#44; <span class="elsevierStyleItalic">CELSR2</span>&#44; <span class="elsevierStyleItalic">PSRC1</span>&#44; <span class="elsevierStyleItalic">MYBPHL</span>&#44; <span class="elsevierStyleItalic">SYP2</span> and <span class="elsevierStyleItalic">SORT1</span>&#46; They found that in human liver the minor allele for the rs646776 SNP was associated with increased expression of the <span class="elsevierStyleItalic">SORT1</span>&#44; <span class="elsevierStyleItalic">CELSR2</span> and <span class="elsevierStyleItalic">PSRC1</span> genes&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> with the strongest association observed for <span class="elsevierStyleItalic">SORT1</span> mRNA levels and its corresponding protein&#44; sortilin&#46; Fine mapping of the region of interest led to the identification of the haplotypes defined by the SNPs present in 6&#46;1 kilobases located between the <span class="elsevierStyleItalic">CELSR2</span> and <span class="elsevierStyleItalic">PSRC1</span> genes&#44; and to the identification of the SNP rs12740374 as the one ultimately responsible for the association observed in GWAS&#46; Bioinformatic analysis showed that&#44; altering the wild-type sequence from G<span class="elsevierStyleBold">G</span>TGCTCAAT to G<span class="elsevierStyleBold">T</span>TGCTCAAT&#44; the minor allele of this variant created a binding site for the CCAAT&#47;enhancer binding protein &#40;C&#47;EBP&#41; &#945;&#44; increasing promoter activity and <span class="elsevierStyleItalic">SORT1</span> expression level&#46; This was later confirmed in vitro&#46; It should be noted that these results are in full agreement with the findings of Linsel-Nitsche&#39;s group<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> concerning mRNA expression levels in the liver&#46; Finally&#44; through studies on liver cells from mutant mice in which the gene coding for sortilin was over-expressed or inactivated&#44; Musunuru et al&#46; demonstrated that sortilin expression levels modulate the hepatic secretion of VLDL&#46; The transgenic mouse chosen by this team was <span class="elsevierStyleItalic">Apobec1</span><span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#44; a humanized mouse in which the gene that encodes the C-&#62;U-editing enzyme APOBEC-1 is suppressed&#44; with a lipid profile closer to that seen in humans&#44; in whom LDL is the predominant cholesterol transporter in circulation&#44; rather than that typical of mice&#46; When Musunuru et al&#46; over-expressed the <span class="elsevierStyleItalic">SORT1</span> gene in <span class="elsevierStyleItalic">Apobec1</span><span class="elsevierStyleSup">&#8722;&#47;&#8722;</span> liver cells&#44; a 70&#37; reduction in plasma total cholesterol &#40;TC&#41; and LDL-C was observed&#46; Similarly&#44; inactivation of <span class="elsevierStyleItalic">SORT1</span> by short-interfering RNA &#40;siRNA&#41; led to increases of 46&#37; in TC and 125&#37; in LDL&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">In general&#44; the data presented by these two teams support the findings of GWAS findings and reinforce the idea of a negative correlation between <span class="elsevierStyleItalic">SORT1</span> mRNA levels and plasma LDL-C concentrations&#46; However&#44; in the same year a third mechanistic study addressing this association was published and in this case&#44; the results were not so easily reconciled either with the results from the previous studies or with the previous assumptions inferred through GWAS&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The results presented by Kjolby et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> were published almost simultaneously&#46; These authors used as a model a double knockout mouse&#44; <span class="elsevierStyleItalic">Sort1</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#8722;&#47;&#8722;</span></span>&#44;<span class="elsevierStyleItalic">Ldlr</span><span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#44; having observed that its hepatocytes presented reductions of 30&#37; in TC levels&#44; &#8764;50&#37; in proteins containing apo B100 &#40;VLDL and LDL&#41;&#44; and &#8764;60&#37; in atherosclerotic plaque area compared to <span class="elsevierStyleItalic">Ldlr</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">&#8722;&#47;&#8722;</span></span> single knockout mice&#46; Next&#44; they performed liver-specific <span class="elsevierStyleItalic">SORT1</span> over-expression&#46; Briefly&#44; they found that sortilin deficiency led to a 50&#37; reduction in the secretion of lipoproteins&#44; whereas over-expression resulted in a 50&#37; increase&#46; Together&#44; these results indicate a positive correlation between <span class="elsevierStyleItalic">SORT1</span> expression and LDL-C levels&#44; opposite to that observed by Musunuru et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Spot the differences&#58; analysis of the results</span><p id="par0165" class="elsevierStylePara elsevierViewall">The question of the discrepancy between the results of these three studies has been discussed by various experts&#44; particularly Dub&#233;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> and Tall and Ai&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> in 2011&#46; These authors drew attention to the methodological differences between the studies of Linsel-Nitschke et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Musunuru et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and Kjolby et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and the effects that those differences may have had on their results&#46; The three teams that set out to clarify the mechanism by which the 1p13 locus affects LDL levels and the risk of CAD opted for different experimental models&#44; which appear to have influenced the final results&#46; This implies that their conclusions&#44; even though they are consistent and resulted from well-designed and consistent experiments&#44; may not be comparable&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The first important point is the metabolic background in which each of the experiments was carried out&#46; Linsel-Nitschke and colleagues<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> conducted their investigation only in humans&#44; unlike Musunuru et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> and Kjolby et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> who analyzed non-human animal models&#46; Nevertheless&#44; the latter teams chose mouse models with different metabolic profiles&#58; Musunuru et al&#46; worked with liver cells from a humanized mouse&#44; <span class="elsevierStyleItalic">Apobec</span><span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#44; while Kjolby et al&#46; studied a sortilin and LDL receptor double knockout &#40;<span class="elsevierStyleItalic">Sort1</span><span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#44;<span class="elsevierStyleItalic">Ldlr</span><span class="elsevierStyleSup">&#8722;&#47;&#8722;</span>&#41;&#46; Musunuru&#39;s mouse produced and secreted abnormally high amounts of lipoproteins&#44; mimicking the human lipid profile&#44; which may have artificially modified sortilin&#39;s secretory pathways and availability&#46; Kjolby&#39;s mouse had deficient lipoprotein catabolism&#44; created by the repression of <span class="elsevierStyleItalic">SORT1</span> expression within hepatocytes and a high-fat &#8220;western&#8221; diet&#46; Finally&#44; there are differences in gene regulation between the two species&#44; man and mouse&#44; as demonstrated by the absence of the C&#47;EBP&#945; binding site in mice&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;37</span></a> This may hinder extrapolation of mouse studies to humans with regard to sortilin&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">It should be noted that&#44; taken together&#44; in vivo observations from studies in mouse models show that sortilin assumes complementary liver functions&#44; depending on the metabolic milieu in which it operates&#44; and ultimately regulates VLDL secretion&#46; The different results reviewed here seem to suggest that sortilin regulates VLDL secretion and traffic to the lysosome when intracellular apo B-100 levels are extremely high&#46; Conversely&#44; at low apo B-100 expression levels&#44; sortilin regulates the formation and secretion of VLDL&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#44;34</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Nevertheless&#44; this putative role of sortilin in the formation and secretion of VLDL is hard to reconcile with GWAS results indicating a specific association with LDL-C but not with triglycerides&#44; which are the major components of VLDL particles&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Taken together&#44; even though the findings of these studies are in some ways contradictory&#44; they also provide strong evidence of the existence of a novel regulatory pathway for lipoprotein metabolism and show that modulating this pathway could alter cardiovascular disease risk in humans&#46; Nevertheless&#44; there is still a long way to go before the whole process and its modulators are clearly understood&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusion</span><p id="par0190" class="elsevierStylePara elsevierViewall">By genotyping high-frequency alleles&#44; GWAS are limited to identifying alleles which exert minimal&#44; or even negligible&#44; effects on the phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Furthermore&#44; the most common alleles appear to explain only a small portion of the phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Thus&#44; a significant proportion of the inheritance of complex phenotypes such as cardiovascular disease &#40;CAD in particular&#41; remains unknown&#44; despite all the efforts in this area through numerous GWAS&#46; This portion of heredity has been called &#8220;missing heritability&#8221; or the &#8220;dark matter&#8221; of heritability&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> The supporters of GWAS argue that increasing the size of the study samples and SNP density will enable detection of alleles with very small effect sizes&#44; revealing the portion of inheritance which remains unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Nevertheless&#44; some authors support an alternative strategy based on whole-genome direct sequencing as a way of identifying rare alleles with large effects on the phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Crucial to this are recent advances in DNA sequencing technology&#44; with the development of new platforms for third-generation sequencing that enable low-cost whole genome sequencing and identification of rare and&#47;or new variants&#46; It is believed that each genome has approximately 10 000 non-synonymous variants&#44; among approximately 3&#46;5 million SNPs&#46; Given the size of these numbers&#44; this kind of sequencing is expected to dominate genetic studies in coming years&#44; a trend that can already be seen&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#8211;45</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">It does&#44; however&#44; appear that the &#8220;dark matter&#8221; of heritability is the product of complex interactions between factors of different types&#58; genetic&#44; genomic and epigenetic&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;46</span></a> Similarly&#44; the phenotype is also the result of nonlinear and stochastic interactions between different genetic and non-genetic factors&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Nevertheless&#44; the discovery and systematization of new genetic variants associated with a particular complex phenotype is important&#44; particularly for the example reported here&#44; in which these techniques have led to the discovery of a previously unknown molecular pathway&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">The three reports reviewed here are exemplary approaches to the need to move from a &#8220;blind&#8221; statistical association given by GWAS to a mechanistic explanation of how a particular genetic variation can modulate a particular phenotype&#46; In this case&#44; GWAS results pointed to a particular starting point&#44; the 1p13 locus&#44;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;21&#8211;23</span></a> which eventually caught the attention of three independent teams who relied on different experimental approaches to unveil the basis of the statistical association&#44; all of which identified the <span class="elsevierStyleItalic">SORT1</span> gene as the modulator of LDL-C levels and MI risk&#46; But&#44; while their results were in agreement concerning the relevance of <span class="elsevierStyleItalic">SORT1</span>&#39;s role in the regulation of lipoprotein metabolism&#44; their interpretations of the effect of its expression on plasma LDL-C levels and its underlying mechanism differed&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Linsel-Nitschke and colleagues<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> proposed&#44; on the basis of their observations&#44; that overexpression of sortilin increases the internalization of LDL&#44; with a consequent decrease in plasma levels&#46; Soon afterwards&#44; through studies in human cohorts&#44; hepatocytes and mice&#44; Musunuru et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> reported an inverse relationship between sortilin expression and circulating LDL-C levels&#44; and proposed an explanatory mechanism through transcriptional regulation &#40;liver-specific&#41; of the <span class="elsevierStyleItalic">SORT1</span> gene by the transcription factor C&#47;EBP&#945;&#46; By contrast&#44; Kjolby et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> observed a direct relationship between <span class="elsevierStyleItalic">SORT1</span> expression and circulating LDL concentrations&#44; suggesting this could result from increased VLDL secretion&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Several explanations have been put forward for the discrepancy between these results&#59; the answer seems to depend on sortilin itself&#44; which appears to be a multifaceted protein that can assume different functions depending on circumstances&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">To summarize&#44; the studies reviewed here presented strong evidence that <span class="elsevierStyleItalic">SORT1</span> is a regulator of plasma LDL-C levels&#44; adding a significant role to the sortilin-coding gene that was unknown until recently&#46; The cellular pathway relating sortilin to lipid metabolism is still controversial but it is surely an issue that will be further explored&#46; A full understanding of this pathway will be crucial to assess whether sortilin is a potential target for therapeutic interventions for hypercholesterolemia or CAD &#40;reviewed in <a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;35</span></a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of interest</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "xres298804"
          "titulo" => "Abstract"
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          "titulo" => "Keywords"
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          "identificador" => "xpalclavsec281829"
          "titulo" => "Palavras-chave"
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        4 => array:3 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0010"
              "titulo" => "Looking for a needle in a haystack&#58; genome-wide association studies"
            ]
            1 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Usual and unusual suspects&#58; low-density lipoprotein cholesterol and sortilin"
            ]
            2 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "An exemplary approach&#58; mechanistic analyses"
            ]
            3 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Spot the differences&#58; analysis of the results"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Conclusion"
        ]
        6 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Conflicts of interest"
        ]
        7 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-01-11"
    "fechaAceptado" => "2013-02-21"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec281828"
          "palabras" => array:6 [
            0 => "Genome-wide association studies"
            1 => "Coronary artery disease"
            2 => "Low-density lipoprotein cholesterol"
            3 => "Sortilin"
            4 => "Functional genetics"
            5 => "Lipoprotein metabolism"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec281829"
          "palabras" => array:6 [
            0 => "<span class="elsevierStyleItalic">Genome wide association studies</span>"
            1 => "Doen&#231;a das art&#233;rias coron&#225;rias"
            2 => "Colesterol lipoprote&#237;na de baixa densidade"
            3 => "Sortilina"
            4 => "Gen&#243;mica funcional"
            5 => "Metabolismo das lipoprote&#237;nas"
          ]
        ]
      ]
    ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Plasma low-density lipoprotein cholesterol &#40;LDL-C&#41; levels are a key determinant of the risk of cardiovascular disease&#44; which is why many studies have attempted to elucidate the pathways that regulate its metabolism&#46; Novel latest-generation sequencing techniques have identified a strong association between the 1p13 locus and the risk of cardiovascular disease caused by changes in plasma LDL-C levels&#46; As expected for a complex phenotype&#44; the effects of variation in this locus are only moderate&#46; Even so&#44; knowledge of the association is of major importance&#44; since it has unveiled a new metabolic pathway regulating plasma cholesterol levels&#46; Crucial to this discovery was the work of three independent teams seeking to clarify the biological basis of this association&#44; who succeeded in proving that <span class="elsevierStyleItalic">SORT1</span>&#44; encoding sortilin&#44; was the gene in the 1p13 locus involved in LDL metabolism&#46; <span class="elsevierStyleItalic">SORT1</span> was the first gene identified as determining plasma LDL levels to be mechanistically evaluated and&#44; although the three teams used different&#44; though appropriate&#44; experimental methods&#44; their results were in some ways contradictory&#46; Here we review all the experiments that led to the identification of the new pathway connecting sortilin with plasma LDL levels and risk of myocardial infarction&#46; The regulatory mechanism underlying this association remains unclear&#44; but its discovery has paved the way for considering previously unsuspected therapeutic targets and approaches&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">O n&#237;vel plasm&#225;tico de c-LDL constitui um determinante chave para o risco de doen&#231;a cardiovascular&#44; raz&#227;o pela qual muitos estudos t&#234;m procurado elucidar as vias que regulam o seu metabolismo&#46; As novas t&#233;cnicas de sequencia&#231;&#227;o de &#250;ltima gera&#231;&#227;o permitiram identificar um forte sinal de associa&#231;&#227;o entre o <span class="elsevierStyleItalic">locus</span> 1p13 e o risco de doen&#231;a cardiovascular causada por altera&#231;&#227;o dos n&#237;veis de LDL no plasma&#46; Como seria de esperar para um fen&#243;tipo complexo&#44; os efeitos da varia&#231;&#227;o nesse <span class="elsevierStyleItalic">locus</span> s&#227;o apenas moderados&#44; ainda assim&#44; o conhecimento da associa&#231;&#227;o foi de grande import&#226;ncia uma vez que conduziu &#224; descoberta de uma nova via metab&#243;lica reguladora dos n&#237;veis de colesterol no plasma&#46; Para tal&#44; foram fundamentais os trabalhos efetuados por tr&#234;s equipas independentes&#44; que ao procurarem esclarecer as bases biol&#243;gicas da associa&#231;&#227;o em causa conseguiram provar que o gene <span class="elsevierStyleItalic">SORT1</span>&#44; codificador da sortilina&#44; era o gene do <span class="elsevierStyleItalic">locus</span> 1p13 implicado no metabolismo das LDL&#46; <span class="elsevierStyleItalic">SORT1</span> foi o primeiro dos genes identificados como determinantes dos n&#237;veis plasm&#225;ticos de LDL a ser alvo de avalia&#231;&#227;o mecan&#237;stica e embora cada uma das equipas recorresse a metodologias experimentais diferentes&#44; mas igualmente apropriadas face &#224; quest&#227;o em investiga&#231;&#227;o&#44; os resultados que obtiveram foram contradit&#243;rios em alguns aspetos&#46; Neste trabalho&#44; revemos o caminho percorrido at&#233; &#224; descoberta da nova via que relaciona a sortilina com os n&#237;veis plasm&#225;ticos de LDL e com o risco de enfarte do mioc&#225;rdio&#46; Ainda por esclarecer permanece o mecanismo regulador dessa liga&#231;&#227;o&#44; mas a sua descoberta sugere novos alvos terap&#234;uticos at&#233; h&#225; bem pouco tempo desconhecidos&#46;</p>"
      ]
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Coutinho MF&#44; Bourbon M&#44; Prata MJ&#44; et al&#46; Sortilina e risco de doen&#231;a cardiovascular&#46; Rev Port Cardiol&#46; 2013&#59;32&#58;793&#8211;799&#46;</p>"
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    ]
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      0 => array:3 [
        "identificador" => "nom0005"
        "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0025">List of abbreviations</span>"
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          0 => array:1 [
            "definicion" => array:18 [
              0 => array:2 [
                "termino" => "apo"
                "descripcion" => "<p id="par0005" class="elsevierStylePara elsevierViewall">apolipoprotein</p>"
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              1 => array:2 [
                "termino" => "C&#47;EBP"
                "descripcion" => "<p id="par0010" class="elsevierStylePara elsevierViewall">CCAAT&#47;enhancer binding protein</p>"
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              2 => array:2 [
                "termino" => "CAD"
                "descripcion" => "<p id="par0015" class="elsevierStylePara elsevierViewall">coronary artery disease</p>"
              ]
              3 => array:2 [
                "termino" => "CVD"
                "descripcion" => "<p id="par0020" class="elsevierStylePara elsevierViewall">cerebrovascular disease</p>"
              ]
              4 => array:2 [
                "termino" => "GLUT4"
                "descripcion" => "<p id="par0025" class="elsevierStylePara elsevierViewall">glucose transporter 4</p>"
              ]
              5 => array:2 [
                "termino" => "GM2AP"
                "descripcion" => "<p id="par0030" class="elsevierStylePara elsevierViewall">GM2 activator protein</p>"
              ]
              6 => array:2 [
                "termino" => "GWAS"
                "descripcion" => "<p id="par0035" class="elsevierStylePara elsevierViewall">genome-wide association studies</p>"
              ]
              7 => array:2 [
                "termino" => "HDL"
                "descripcion" => "<p id="par0040" class="elsevierStylePara elsevierViewall">high-density lipoprotein</p>"
              ]
              8 => array:2 [
                "termino" => "LDL"
                "descripcion" => "<p id="par0045" class="elsevierStylePara elsevierViewall">low-density lipoprotein</p>"
              ]
              9 => array:2 [
                "termino" => "LDL-C"
                "descripcion" => "<p id="par0050" class="elsevierStylePara elsevierViewall">low-density lipoprotein</p>"
              ]
              10 => array:2 [
                "termino" => "LPL"
                "descripcion" => "<p id="par0055" class="elsevierStylePara elsevierViewall">lipoprotein lipase</p>"
              ]
              11 => array:2 [
                "termino" => "MI"
                "descripcion" => "<p id="par0060" class="elsevierStylePara elsevierViewall">myocardial infarction</p>"
              ]
              12 => array:2 [
                "termino" => "RAP"
                "descripcion" => "<p id="par0065" class="elsevierStylePara elsevierViewall">receptor-associated protein</p>"
              ]
              13 => array:2 [
                "termino" => "SAP"
                "descripcion" => "<p id="par0070" class="elsevierStylePara elsevierViewall">sphingolipid activator protein</p>"
              ]
              14 => array:2 [
                "termino" => "siRNA"
                "descripcion" => "<p id="par0075" class="elsevierStylePara elsevierViewall">short interfering RNA</p>"
              ]
              15 => array:2 [
                "termino" => "SNP"
                "descripcion" => "<p id="par0080" class="elsevierStylePara elsevierViewall">single-nucleotide polymorphism</p>"
              ]
              16 => array:2 [
                "termino" => "TC"
                "descripcion" => "<p id="par0085" class="elsevierStylePara elsevierViewall">total cholesterol</p>"
              ]
              17 => array:2 [
                "termino" => "VLDL-C"
                "descripcion" => "<p id="par0090" class="elsevierStylePara elsevierViewall">very low-density lipoprotein cholesterol</p>"
              ]
            ]
          ]
        ]
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                    0 => array:2 [
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                            0 => "W&#46; Rosamond"
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                    0 => array:2 [
                      "doi" => "10.1161/CIRCULATIONAHA.106.179918"
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                          "etal" => false
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                      "titulo" => "Incidence and prevalence of hypercholesterolemia in Portugal&#58; a systematic review"
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                          "etal" => true
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                            1 => "M&#46; Borges"
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                        0 => array:3 [
                          "colaboracion" => "Investigators of the Portuguese FH Study"
                          "etal" => true
                          "autores" => array:3 [
                            0 => "A&#46;M&#46; Medeiros"
                            1 => "A&#46;C&#46; Alves"
                            2 => "V&#46; Francisco"
                          ]
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                          "etal" => false
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                        "fecha" => "2006"
                        "volumen" => "7"
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2013.10.024

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2024 July	32	40	72
2024 June	50	33	83
2024 May	115	26	141
2024 April	43	23	66
2024 March	37	24	61
2024 February	27	32	59
2024 January	43	34	77
2023 December	35	27	62
2023 November	35	23	58
2023 October	25	20	45
2023 September	24	19	43
2023 August	29	22	51
2023 July	40	8	48
2023 June	91	17	108
2023 May	53	25	78
2023 April	25	7	32
2023 March	45	24	69
2023 February	38	22	60
2023 January	18	15	33
2022 December	38	26	64
2022 November	37	33	70
2022 October	37	18	55
2022 September	31	41	72
2022 August	28	42	70
2022 July	25	35	60
2022 June	28	26	54
2022 May	29	34	63
2022 April	28	26	54
2022 March	27	25	52
2022 February	34	22	56
2022 January	53	31	84
2021 December	24	39	63
2021 November	36	34	70
2021 October	40	40	80
2021 September	31	37	68
2021 August	49	41	90
2021 July	30	30	60
2021 June	34	15	49
2021 May	28	43	71
2021 April	41	30	71
2021 March	71	17	88
2021 February	64	10	74
2021 January	40	13	53
2020 December	54	13	67
2020 November	30	11	41
2020 October	21	8	29
2020 September	62	6	68
2020 August	27	10	37
2020 July	55	5	60
2020 June	50	2	52
2020 May	61	4	65
2020 April	62	9	71
2020 March	49	6	55
2020 February	71	15	86
2020 January	32	4	36
2019 December	38	2	40
2019 November	45	4	49
2019 October	27	3	30
2019 September	41	10	51
2019 August	25	1	26
2019 July	25	9	34
2019 June	42	6	48
2019 May	29	3	32
2019 April	25	14	39
2019 March	36	9	45
2019 February	43	13	56
2019 January	36	3	39
2018 December	65	8	73
2018 November	120	9	129
2018 October	234	18	252
2018 September	67	9	76
2018 August	45	9	54
2018 July	36	6	42
2018 June	41	8	49
2018 May	56	11	67
2018 April	106	7	113
2018 March	41	9	50
2018 February	29	4	33
2018 January	33	8	41
2017 December	38	12	50
2017 November	16	4	20
2017 October	26	12	38
2017 September	29	12	41
2017 August	43	9	52
2017 July	30	8	38
2017 June	44	5	49
2017 May	65	8	73
2017 April	26	1	27
2017 March	29	36	65
2017 February	31	5	36
2017 January	28	2	30
2016 December	25	11	36
2016 November	23	3	26
2016 October	48	2	50
2016 September	19	6	25
2016 August	9	0	9
2016 July	11	2	13
2016 June	12	2	14
2016 May	14	3	17
2016 April	34	2	36
2016 March	75	24	99
2016 February	92	27	119
2016 January	50	18	68
2015 December	53	24	77
2015 November	49	22	71
2015 October	53	26	79
2015 September	61	19	80
2015 August	60	20	80
2015 July	42	20	62
2015 June	24	8	32
2015 May	46	15	61
2015 April	50	30	80
2015 March	54	19	73
2015 February	39	12	51
2015 January	35	16	51
2014 December	75	19	94
2014 November	57	13	70
2014 October	69	16	85
2014 September	61	10	71
2014 August	61	12	73
2014 July	68	12	80
2014 June	72	11	83
2014 May	58	18	76
2014 April	46	6	52
2014 March	72	30	102
2014 February	66	24	90
2014 January	68	27	95
2013 December	23	12	35

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