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Effects of common genetic variants associated with type 2 diabetes and glycemic traits on ?- and ?-cell function and insulin action in humans.

ABSTRACT: Although meta-analyses of genome-wide association studies have identified >60 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes and/or glycemic traits, there is little information on whether these variants also affect ?-cell function. The aim of the current study was to evaluate the effects of glycemia-associated genetic loci on islet function in vivo and in vitro. We studied 43 SNPs in 4,654 normoglycemic participants from the Finnish population-based Prevalence, Prediction, and Prevention of Diabetes-Botnia (PPP-Botnia) Study. Islet function was assessed, in vivo, by measuring insulin and glucagon concentrations during oral glucose tolerance test, and, in vitro, by measuring glucose-stimulated insulin and glucagon secretion from human pancreatic islets. Carriers of risk variants in BCL11A, HHEX, ZBED3, HNF1A, IGF1, and NOTCH2 showed elevated whereas those in CRY2, IGF2BP2, TSPAN8, and KCNJ11 showed decreased fasting and/or 2-h glucagon concentrations in vivo. Variants in BCL11A, TSPAN8, and NOTCH2 affected glucagon secretion both in vivo and in vitro. The MTNR1B variant was a clear outlier in the relationship analysis between insulin secretion and action, as well as between insulin, glucose, and glucagon. Many of the genetic variants shown to be associated with type 2 diabetes or glycemic traits also exert pleiotropic in vivo and in vitro effects on islet function.

SUBMITTER: Jonsson A

PROVIDER: S-EPMC3717852 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Effects of common genetic variants associated with type 2 diabetes and glycemic traits on α- and β-cell function and insulin action in humans.

Jonsson Anna A Ladenvall Claes C Ahluwalia Tarunveer Singh TS Kravic Jasmina J Krus Ulrika U Taneera Jalal J Isomaa Bo B Tuomi Tiinamaija T Renström Erik E Groop Leif L Lyssenko Valeriya V

Diabetes 20130404 8

Although meta-analyses of genome-wide association studies have identified >60 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes and/or glycemic traits, there is little information on whether these variants also affect α-cell function. The aim of the current study was to evaluate the effects of glycemia-associated genetic loci on islet function in vivo and in vitro. We studied 43 SNPs in 4,654 normoglycemic participants from the Finnish population-based Prevalence, Prediction ...[more]

PMID: 23557703

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Project description:Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (?200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P < 4.13 × 10-7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10-9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B. Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.

Dataset Information

Effects of common genetic variants associated with type 2 diabetes and glycemic traits on ?- and ?-cell function and insulin action in humans.

Publications

Effects of common genetic variants associated with type 2 diabetes and glycemic traits on α- and β-cell function and insulin action in humans.

Similar Datasets

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