Association of the C825T polymorphism of the G-protein β3 subunit gene with hypertension, obesity, hyperlipidemia, insulin resistance, diabetes, diabetic complications, and diabetic therapies among Japanese
Introduction
G proteins are signal transducers that communicate signals from many hormones, neurotransmitters, chemokines, and autocrine and paracrine factors [1]. A C825T polymorphism of the gene encoding the G-protein β3 subunit (GNB3) is associated with the occurrence of alternative splicing, which causes the loss of 41 amino acids. This polymorphism is associated with increased intracellular signal transduction [2]. The 825T allele possibly increases the risk for phenotypes of metabolic syndromes. Siffert et al [2] have shown that the C825T polymorphism is significantly associated with essential hypertension in Germans. A significant association of the 825T allele with an increased body mass index (BMI) has been observed in Germans, Chinese, and black Africans [3]. Total cholesterol is significantly higher in subjects with the T allele among Japanese [4]. The 825T allele was reported to be predisposed for end-stage renal disease in type 2 diabetes mellitus [5]. The 825T allele frequencies are shown to differ among ethnic groups [3]. The roles of the 825T allele in hypertension, obesity, hyperlipidemia, diabetes, and diabetic complications have been controversial in whites [2], [3], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21] and Japanese [22], [23], [24], [25], [26], [27], [28]. Thus, we investigated how this genetic polymorphism in the GNB3 is associated with hypertension, obesity, hyperlipidemia, diabetic complications, and diabetic therapies among Japanese.
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Subjects and methods
A total of 427 Japanese subjects with type 2 diabetes mellitus, aged from 20 to 89 years (60.5 ± 11.9 years, mean ± SD), were recruited from among patients admitted to the Kanazawa Municipal Hospital (Kanazawa, Japan) for diabetic treatment. Type 2 diabetes was defined by the World Health Organization criteria [29]. There were a total of 251 men and 176 women. Obese or nonobese status was diagnosed by the criteria of the Japan Society for the Study of Obesity. In the present BMI, 298 were
Results
Among the subjects with diabetes, 124 (29.0%) were CC homozygotes (CC), 197 (46.1%) were CT heterozygotes (CT), and 106 (24.8%) were TT homozygotes (TT). The frequency of the T allele was 0.48. Among the subjects who had general health examinations, 104 (22.8%) were CC, 180 (48.9%) were CT, and 104 (28.3%) were TT. The frequency of the T allele was 0.47. In the control group, the frequency of the T allele was 0.47. No significant differences were observed between subjects with diabetes and the
Discussion
G proteins relay signals from each of more than 1000 receptors to many different effectors, including enzymes and ion channels. The G proteins are composed of an α subunit that is loosely bound to a tightly associated structure made up of a β subunit and a γ subunit. The activity of the trimeric G protein is regulated by the binding and hydrolysis of guanosine triphosphate by the G α subunit. An α subunit to which guanosine diphosphate is bound is inactive and associates with the βγ dimer [31].
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2014, Cellular SignallingCitation Excerpt :This polymorphism was initially identified in patients with essential hypertension; and later population-based association studies linked Gβ3s to diverse disorders, including obesity, diabetes, depression, and tumors [24–27]. For many of these studies, however, the results are inconsistent and in many cases contradictory [28–33]. The initial characterization of Gβ3s by Siffert's group suggested that Gβ3s was a gain-of-function mutant with enhanced activity both in promoting GPCR-mediated Gα activation and stimulating Gβγ effectors [22,23].
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2012, Pharmacological ReportsCitation Excerpt :However, the T allele is in almost complete linkage disequilibrium with a series of other polymorphisms within the GNB3 gene, the so-called ‘T-haplotype’, which is associated with deletion of nucleotides 498–620 of exon 9, due to alternative splicing. It has been shown that this splice variant is functional and is postulated to be associated with enhanced signaling activity [6]. The GNB3 825T allele was observed more frequently in patients with essential hypertension, obesity, left ventricular hypertrophy and in subjects with lower renin plasma activity [7, 14].
Effects of C825T polymorphism of the GNB3 gene on availability of dopamine transporter in healthy volunteers - A SPECT study
2011, NeuroImageCitation Excerpt :Further study would be useful in order to investigate the underlying mechanism and interactions between dopamine transporters, receptors, and the downstream G-protein in the striatum. The SNP C825T of the GNβ3 gene has been reported to be associated with elevated metabolic indexes in different groups of patients suffering from hypertension, diabetes or cardiovascular disease (Brand et al., 2003; Casiglia et al., 2008; Danoviz et al., 2006; Hayakawa et al., 2007; Kopf et al., 2008; Meirhaeghe et al., 2005). Moreover, the variant has also been found to be associated with medication-induced metabolic disturbances (Hauner et al., 2003; Peters et al., 2008; Souza et al., 2008; Wang et al., 2005).
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