A genetic variant of G6PC2 is associated with type 2 diabetes and fasting plasma glucose level in the Chinese population

Abstract

Aims/hypothesis Single nucleotide polymorphisms (SNPs) in G6PC2 have been reported to be associated with fasting plasma glucose level in several populations of European descent. However, whether G6PC2 variants have a similar effect in other ethnic groups is unknown. The aim of this study was to investigate the effect of common variants of G6PC2 on type 2 diabetes and related clinical features in a Chinese population. Methods We selected four SNPs, rs13387347, rs2232316, rs492594 and rs16856187, tagging all the common variants spanning the G6PC2 gene (r 2 ≥0.8) based on HapMap Chinese data, and genotyped them in a group of 3,676 Shanghai Chinese individuals, comprising 1,876 cases and 1,800 controls. Results Three SNPs were nominally associated with type 2 diabetes, with rs16856187 showing the strongest evidence for association (p=0.0009, empirical p=0.0047). Further conditional analysis revealed that the association signal arose from an individual SNP, rs16856187. This SNP was also associated with fasting plasma glucose level in participants with normal glucose regulation (p=0.0002), with the fasting plasma glucose level observed to increase by 0.067 mmol/l with each copy of the rare C allele. Conclusions/interpretation In this study we identified a novel risk-conferring G6PC2 SNP for type 2 diabetes in a Chinese population and confirmed the previous finding that G6PC2 variants are associated with fasting plasma glucose concentration.

Effects of G6pc2 deletion on body weight and cholesterol in mice

“…Since GWAS data show that the rs560887-G allele is associated with elevated FBG (Bouatia-Naji et al 2008; Chen et al 2008), the combination of these splicing (Baerenwald et al 2013) and G6pc2 KO mouse (Pound et al 2013; Wang et al 2007) studies suggest that rs560887 is a potentially causative variant. The association between G6PC2 and FBG has been confirmed in multiple GWAS and in different populations (Bouatia-Naji, et al 2009; Dupuis, et al 2010; Hu, et al 2009; Hu, et al 2010; Prokopenko, et al 2008; Reiling, et al 2009; Tam, et al 2010; Wang, et al 2013). …”

Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels

“…Genome-wide association studies have recently provided important new insights about the genetics of common forms of type 2 diabetes and some of its related quantitative traits such as FPG and HbA1c [6, 7, 14–18, 39–42]. The studies described here represent a key step in extending these discovery phase GWAS data through the analysis of the functional properties of variants that span the G6PC2 locus (ESM Fig.…”

“…FPG and HbA1c are important metabolic traits that are correlated with the risk of developing type 2 diabetes [8–10] and cardiovascular-associated mortality [11–13]. Multiple other studies have confirmed that the G6PC2 locus harbors the strongest common genetic determinant of FPG levels in terms of significance and effect size, particularly with a common single nucleotide polymorphism (SNP), rs560887, that is located in the third intron of G6PC2 , and that explains ~1% of the total variance in FPG [14–18]. These genetic data are consistent with the ~15% decrease in FPG observed following a global knockout of G6pc2 in mice [4] and support the hypothesis that genetic variation within the G6PC2 gene, rather than surrounding genes, directly contribute to variations in FPG in humans.…”

Association of genetic variants of NOS1AP with type 2 diabetes in a Chinese population

“…In stage 1, we recruited 1,892 unrelated type 2 diabetic patients from the inpatient database of Shanghai Diabetes Institute and 1,808 unrelated controls who had been recruited from the general population by the Shanghai Diabetes Studies [25,26]. In stage 2, we additionally recruited 1,663 type 2 diabetic patients from the Shanghai Diabetes Institute inpatient database and 1,408 controls from the general population in Shanghai.…”