A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population.

HNF1alpha (TCF1) is a key transcription factor that is essential for pancreatic beta-cell development and function. Rare mutations of HNF1alpha cause maturity-onset diabetes of the young. A common variant, G319S, private to the Oji-Cree population, predisposes to type 2 diabetes, but the role of common HNF1alpha variation in European populations has not been comprehensively assessed. We determined the linkage disequilibrium and haplotype structure across the HNF1alpha gene region using 29 single nucleotide polymorphisms (SNPs). Eight tagging SNPs (tSNPs) that efficiently capture common haplotypes and the amino acid-changing variant, A98V, were genotyped in 5,307 subjects (2,010 type 2 diabetic case subjects, 1,643 control subjects, and 1,654 members of 521 families). We did not find any evidence of association between the tSNPs or haplotypes and type 2 diabetes. We could exclude odds ratios (ORs) >1.25 for all tSNPs. The rare V98 allele (approximately 3% frequency) showed possible evidence of association with type 2 diabetes (OR 1.23 [95% CI 0.99-1.54], P = 0.07), a result that was supported by meta-analysis of this and published studies (OR 1.31 [1.08-1.59], P = 0.007). Further studies are required to investigate this association, demonstrating the difficulty of defining the role of rare (<5%) alleles in type 2 diabetes risk.

[1]  Kristin G Ardlie,et al.  Association of common variation in the HNF1alpha gene region with risk of type 2 diabetes. , 2005, Diabetes.

[2]  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.

[3]  Alan E. Jackson,et al.  Polymorphic variations in the neurogenic differentiation-1, neurogenin-3, and hepatocyte nuclear factor-1alpha genes contribute to glucose intolerance in a South Indian population. , 2004, Diabetes.

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

[5]  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.

[6]  Nicola J. Rinaldi,et al.  Control of Pancreas and Liver Gene Expression by HNF Transcription Factors , 2004, Science.

[7]  J. Gulcher,et al.  Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. , 2003, American journal of human genetics.

[8]  H. Deng,et al.  [Relationship between Ala98Val variant of hepatocyte nuclear factor-1 alpha gene and late-onset type 2 diabetes in Han nationality]. , 2003, Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University.

[9]  L. Chuang,et al.  Transcription factor 1 and β‐cell function in glucose‐tolerant subjects , 2003 .

[10]  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.

[11]  J. Ferrer.  A genetic switch in pancreatic beta-cells: implications for differentiation and haploinsufficiency. , 2002, Diabetes.

[12]  M. McCarthy,et al.  Genomewide search for type 2 diabetes mellitus susceptibility loci in Finnish families: the Botnia study. , 2002, American journal of human genetics.

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

[14]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[15]  L. Niskanen,et al.  Variants in the hepatocyte nuclear factor-1alpha and -4alpha genes in Finnish and Chinese subjects with late-onset type 2 diabetes. , 2000, Diabetes care.

[16]  Eric S. Lander,et al.  The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes , 2000, Nature Genetics.

[17]  L. Chuang,et al.  The I27L amino acid polymorphism of hepatic nuclear factor-1alpha is associated with insulin resistance. , 2000, The Journal of clinical endocrinology and metabolism.

[18]  Gonçalo R. Abecasis,et al.  GOLD-Graphical Overview of Linkage Disequilibrium , 2000, Bioinform..

[19]  Xin Xu,et al.  Implementing a unified approach to family‐based tests of association , 2000, Genetic epidemiology.

[20]  M. McCarthy,et al.  Parent-offspring trios: a resource to facilitate the identification of type 2 diabetes genes. , 1999, Diabetes.

[21]  C. Lindgren,et al.  High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes , 1999, Diabetologia.

[22]  B. Zinman,et al.  The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. , 1999, The Journal of clinical endocrinology and metabolism.

[23]  T. Hansen,et al.  The Ala/Val98 polymorphism of the hepatocyte nuclear factor-1alpha gene contributes to the interindividual variation in serum C-peptide response during an oral glucose tolerance test: evidence from studies of 231 glucose-tolerant first degree relatives of type 2 diabetic probands. , 1998, The Journal of clinical endocrinology and metabolism.

[24]  A. M. Møller,et al.  The effect of two frequent amino acid variants of the hepatocyte nuclear factor-1alpha gene on estimates of the pancreatic beta-cell function in Caucasian glucose-tolerant first-degree relatives of type 2 diabetic patients. , 1998, The Journal of clinical endocrinology and metabolism.

[25]  P. Behn,et al.  Hepatocyte nuclear factor 1alpha coding mutations are an uncommon contributor to early-onset type 2 diabetes in Ashkenazi Jews. , 1998, Diabetes.

[26]  M. Boehnke,et al.  Genetic association mapping based on discordant sib pairs: the discordant-alleles test. , 1998, American journal of human genetics.

[27]  W. Ewens,et al.  A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. , 1998, American journal of human genetics.

[28]  Torben Hansen,et al.  A Prevalent Amino Acid Polymorphism at Codon 98 in the Hepatocyte Nuclear Factor-1α Gene Is Associated With Reduced Serum C-Peptide and Insulin Responses to an Oral Glucose Challenge , 1997, Diabetes.

[29]  A. M. Møller,et al.  Genetic variation in the hepatocyte nuclear factor-1a gene in Danish Caucasians with late-onset NIDDM , 1997, Diabetologia.

[30]  T. Hansen,et al.  Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3) , 1996, Nature.

[31]  M. McCarthy,et al.  Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families , 1996, Nature Genetics.

[32]  K. Kangawa,et al.  High plasma concentrations of human atrial natriuretic polypeptide in aged men. , 1987, The Journal of clinical endocrinology and metabolism.

[33]  B. Haldane.  THE ESTIMATION AND SIGNIFICANCE OF THE LOGARITHM OF A RATIO OF FREQUENCIES , 1956, Annals of human genetics.