Association Studies of Variants in the Genes Involved in Pancreatic β-Cell Function in Type 2 Diabetes in Japanese Subjects

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic β-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2–2, NKX6–1, and NEUROD1) and genes encoding the ATP-sensitive K+ channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 −3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97–1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.

[1]  E. Feskens,et al.  Common variants in the ATP‐sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population‐based studies and meta‐analyses 1 , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[2]  K. Kosaka,et al.  Heterogeneous relationship of early insulin response and fasting insulin level with development of non-insulin-dependent diabetes mellitus in non-diabetic Japanese subjects with or without obesity. , 1999, Diabetes research and clinical practice.

[3]  M. Permutt,et al.  Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR ): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians , 1998, Diabetologia.

[4]  P. de Knijff,et al.  Variants in the sulphonylurea receptor gene: association of the exon 16–3t variant with Type II diabetes mellitus in Dutch Caucasians , 1999, Diabetologia.

[5]  J. Habener,et al.  A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus. , 1998, Proceedings of the Association of American Physicians.

[6]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[7]  M. Permutt,et al.  Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM. , 1998, Diabetes.

[8]  K. Yamada,et al.  Clinical characterization of polymorphisms in the sulphonylurea receptor 1 gene in Japanese subjects with Type 2 diabetes mellitus , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[9]  M. Daly,et al.  Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. , 2004, Diabetes.

[10]  Benjamin Glaser,et al.  A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an ashkenazi jewish population. , 2004, Diabetes.

[11]  K. Clément,et al.  Genetic Studies of the Sulfonylurea Receptor Gene Locus in NIDDM and in Morbid Obesity Among French Caucasians , 1997, Diabetes.

[12]  A. M. Møller,et al.  Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene. , 1998, Diabetes.

[13]  S. Wiltshire,et al.  Association studies of variants in promoter and coding regions of beta‐cell ATP‐sensitive K‐channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53) , 2001, Diabetic medicine : a journal of the British Diabetic Association.

[14]  G I Bell,et al.  Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. , 2001, The New England journal of medicine.

[15]  J. Bryan,et al.  Molecular biology of adenosine triphosphate-sensitive potassium channels. , 1999, Endocrine reviews.

[16]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[17]  S. Wiltshire,et al.  Erratum: Association studies of variants in promoter and coding regions of beta-cell ATP sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53) (Diabetic Medicine (2001) 18 (206-212)) , 2003 .

[18]  M. Permutt,et al.  Sequence Variants in the Sulfonylurea Receptor (SUR) Gene Are Associated With NIDDM in Caucasians , 1996, Diabetes.

[19]  Jacqueline K. Wittke-Thompson,et al.  Rational inferences about departures from Hardy-Weinberg equilibrium. , 2005, American journal of human genetics.

[20]  S. Seino.  ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. , 1999, Annual review of physiology.

[21]  T. Hansen,et al.  Amino Acid Polymorphisms in the ATP-Regulatable Inward Rectifier Kir6.2 and Their Relationships to Glucose- and Tolbutamide-Induced Insulin Secretion, the Insulin Sensitivity Index, and NIDDM , 1997, Diabetes.

[22]  S. Hunt,et al.  Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. , 2004, Diabetes.

[23]  M. McCarthy,et al.  Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. , 2003, Diabetes.

[24]  M. McCarthy,et al.  Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population. , 2004, Diabetes.

[25]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[26]  P. Pearson,et al.  The exon 16–3t variant of the sulphonylurea receptor gene is not a risk factor for Type II diabetes mellitus in the Dutch Breda cohort , 2000, Diabetologia.

[27]  D. Arveiler,et al.  Impact of sulfonylurea receptor 1 genetic variability on non-insulin-dependent diabetes mellitus prevalence and treatment: a population study. , 2001, American journal of medical genetics.

[28]  F. Ashcroft,et al.  Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. , 2004, The New England journal of medicine.

[29]  C. Bellanné-Chantelot,et al.  Association of a variant in exon 31 of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus in French Caucasians , 2000, Human Genetics.

[30]  L. Niskanen,et al.  Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin. , 2000, Diabetes care.