Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study

Abstract

BackgroundMultiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.MethodsAs part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.ResultsOverall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.ConclusionsGeneralization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.

Evaluating the transferability of 15 European-derived fasting plasma glucose SNPs in Mexican children and adolescents

“…Stressing the fact that FPG levels are not influenced by the same factors in children and adults is also important29. Our findings confirm that SNPs previously identified in specific ethnic groups are relevant candidates for association analyses in other populations1112303132.…”

“…This supports the view that the genetic dissection of both extremes of the disease and intermediary quantitative traits is necessary for the understanding of glucose homeostasis9. FPG-associated loci identified in European populations were in part replicated in various ethnic groups101112. Only one study to date have assessed the contribution of GWAS identified European adult FPG-associated loci in a youth population13.…”

Association of African genetic ancestry with fasting glucose and HbA1c levels in non-diabetic individuals: the Boston Area Community Health (BACH) Prediabetes Study

“…Transethnic studies show that genetic determinants of type 2 diabetes risk or glycaemic trait levels in whites also operate in African-Americans, albeit at varying allele frequencies; thus, absolute genetic differences between racial/ethnic groups in glycaemic trait levels or disease risk are generally small [13–18]. For instance, African-American type 2 diabetes admixture mapping is consistent with an independent effect of African ancestry proportion on type 2 diabetes risk but not on diabetes-related quantitative trait levels (such as fasting glucose [FG], insulin or HbA 1c ) in non-diabetic individuals [12].…”

Genome Mapping and Genomics in Human and Non-Human Primates

“…After failing to find association between a number of such genetic risk variants and T2D in African Americans (with the exception of certain variants in the TCF7L2 gene), Lewis et al (2008) concluded that the T2D susceptibility genes in African Americans may, in part, be different from those identified in the European-derived populations. In recent years, there have been continued efforts to examine the transferability of the established GWAS T2D and/ or glycemic trait loci in the US multiethnic populations with considerable affirmations Haiman et al 2012;Fesinmeyer et al 2013;. In recent years, there have been continued efforts to examine the transferability of the established GWAS T2D and/ or glycemic trait loci in the US multiethnic populations with considerable affirmations Haiman et al 2012;Fesinmeyer et al 2013;.…”