Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic β-Cell KATP Channel Subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) Confirm That the KCNJ11 E23K Variant Is Associated With Type 2 Diabetes

Gloyn, Anna L.; Weedon, Michael N.; Owen, Katharine R.; Turner, Martina; Knight, Bridget; Hitman, G. A.; Walker, Mark; Levy, Jonathan C.; Sampson, Mike; Halford, Stephanie; McCarthy, Mark I.; Hattersley, Andrew T.; Frayling, Timothy M.

doi:10.2337/diabetes.52.2.568

Cited by 686 publications

(451 citation statements)

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“…Frequently, these samples are not available in a single study, and meta-analysis is used to pool together the results from several different studies. In type 2 diabetes, meta-analysis has been used successfully to establish the role of risk alleles for type 2 diabetes [16][17][18][19]. Towards this end, we have combined results from genotyping the Gly482Ser variant in our current study with those from available published studies and performed a meta-analysis of the dataset.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

et al. 2006

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Aims/hypothesis: Peroxisome proliferator-activated receptor-γ co-activator-1α (PPARGC1A) is a transcriptional co-activator with a central role in energy expenditure and glucose metabolism. Several studies have suggested that the common PPARGC1A polymorphism Gly482Ser may be associated with risk of type 2 diabetes, with conflicting results. To clarify the role of Gly482Ser in type 2 diabetes and related human metabolic phenotypes we genotyped this polymorphism in a case-control study and performed a meta-analysis of relevant published data. Materials and methods: Gly 482Ser was genotyped in a type 2 diabetes case-control study (N=1,096) using MassArray technology. A literature search revealed publications that examined Gly482-Ser for association with type 2 diabetes and related metabolic phenotypes. Meta-analysis of the current study and relevant published data was undertaken. Results: In the pooled meta-analysis, including data from this study and seven published reports (3,718 cases, 4,818 controls), there was evidence of between-study heterogeneity (p<0.1). In the fixed-effects meta-analysis, the pooled odds ratio for risk of type 2 diabetes per Ser482 allele was 1.07 (95% CI 1.00-1.15, p=0.044). Elimination of one of the studies from the meta-analysis gave a summary odds ratio of 1.11 (95% CI 1.04-1.20, p=0.004), with no between-study heterogeneity (p=0.475). For quantitative metabolic traits in normoglycaemic subjects, we also found significant between-study heterogeneity. However, no significant association was observed between Gly482-Ser and BMI, fasting glucose or fasting insulin. Conclusions/ interpretation: This meta-analysis of data from the current and published studies supports a modest role for the Gly482Ser PPARGC1A variant in type 2 diabetes risk.

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Section: Introductionmentioning

confidence: 99%

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

et al. 2006

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“…Two representative common variants (KCNJ11 E23K and ABCC8 exon16-3t/c), which were in different LD blocks, have also been reported to be associated with type 2 diabetes in various ethnic populations, with fairly consistent results for the KCNJ11 E23K variant and conflicting results for the ABCC8 exon16-3t/c variant. [1][2][3][4] However, a large-scale association study of these genes has not been carried out in the Chinese Han population; and there was much inconsistency in results in East Asian studies before. [5][6][7][8][9] …”

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The E23K variation in the KCNJ11 gene is associated with type 2 diabetes in Chinese and East Asian population

et al. 2009

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The genes (ABCC8 and KCNJ11) have a key role in glucose-stimulated insulin secretion and thus have always been considered as excellent susceptibility candidates for involvement in type 2 diabetes. Common polymorphisms (KCNJ11 E23K and ABCC8 exon16-3t/c) in these genes have been reported to be associated with type 2 diabetes in various European-descent populations. However, there were inconsistent results in previous studies in East Asian populations and no large case-control studies have been carried out in the Chinese Han population. In this study, these two variants were genotyped in about 4000 Chinese by using TaqMan technology on an ABI7900 system. A meta-analysis was also used to assess the results of association between the two variants and type 2 diabetes in East Asian populations. Our investigation confirmed the association between the KCNJ11 E23K variant and type 2 diabetes under a recessive model (KK vs EK+EE) in the Chinese Han population (odds ratio (OR)¼1.25, 95% confidence interval (95% CI) 1.04-1.50, P¼0.017). The meta-analysis of East Asian populations also showed a strong significant association of the K allele with diabetes (OR¼1.15, P¼3Â10 À9 ), whereas the exon16-3t/c variant (rs1799854) in ABCC8 showed no significant association. Thus, the common E23K variant is considered as a strong candidate for type 2 diabetes susceptibility across different ethnicities. Keywords: association study; Chinese population; KCNJ11; meta-analysis; type 2 diabetes Type 2 diabetes is a polygenic disorder characterized by defects in insulin secretion and peripheral insulin resistance. The pancreatic b-cell adenosine triphosphate (ATP)-sensitive potassium channel (KATP), which is composed of Kir6.2 subunits (the KCNJ11 gene) and Sur1 subunits (the ABCC8 gene), has a central role in the regulation of glucose-induced insulin secretion by linking signals derived from glucose metabolism to cell membrane depolarization and insulin exocytosis. 1 Mutations in both genes can cause familial persistent hyperinsulinemic hypoglycemia in infancy and permanent neonatal diabetes. The KCNJ11 and ABCC8 genes are located at the same chromosome locus, 11p15.1, and are only 4.5 kb apart. Moreover, the strong linkage disequilibrium (LD) across the KCNJ11 gene also extends into the ABCC8 gene. Two representative common variants (KCNJ11 E23K and ABCC8 exon16-3t/c), which were in different LD blocks, have also been reported to be associated with type 2 diabetes in various ethnic populations, with fairly consistent results for the KCNJ11 E23K variant and conflicting results for the ABCC8 exon16-3t/c variant. [1][2][3][4] However, a large-scale association study of these genes has not been carried out in the Chinese Han population; and there was much inconsistency in results in East Asian studies before. [5][6][7][8][9]

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“…Diabetes was one of the first disease areas to yield results from these genome-wide association studies. Prior to 2006, only two genes were established type 2 diabetes loci (PPARG [1] and KCNJ11 [2]). With the latest round of metaanalyses there are 18 such loci [3,4], probably more by the time this article goes to print.…”

mentioning

confidence: 99%

Translating TCF7L2: from gene to function

Pearson

2009

Diabetologia

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Large-Scale Association Studies of Variants in Genes Encoding the Pancreatic β-Cell KATP Channel Subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) Confirm That the KCNJ11 E23K Variant Is Associated With Type 2 Diabetes

Cited by 686 publications

References 29 publications

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

The E23K variation in the KCNJ11 gene is associated with type 2 diabetes in Chinese and East Asian population

Translating TCF7L2: from gene to function

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