title: Studies in 3,523 Norwegians and meta-analysis in 11,571 subjects indicate that variants in the hepatocyte nuclear factor 4 alpha (HNF4A) P2 region are associated with type 2 diabetes in Scandinavians.
abstract: OBJECTIVE
  Recent publications have found an association between common variants near the hepatocyte nuclear factor 4 alpha (HNF4A) P2 promoter and type 2 diabetes in some populations but not in others, and the role for HNF4A in type 2 diabetes has remained unclear. In an attempt to address these inconsistencies, we investigated HNF4A single nucleotide polymorphisms (SNPs) in a large population-based sample and included a meta-analysis of published studies.
  
  
  METHODS
  We genotyped 12 SNPs in the HNF4A region in a Norwegian population-based sample of 1,644 individuals with type 2 diabetes and 1,879 control subjects (the Nord-Trøndelag Health Study [HUNT] 2). We combined our data with all previously published case/control studies and performed a meta-analysis.
  
  
  RESULTS
  Consistent with initial studies, we found a trend toward association for the SNPs rs1884613 (odds ratio [OR] 1.17 [95% CI 1.03-1.35]) and rs2144908 (1.21 [1.05-1.38]) in the P2 region and for rs4812831 (1.21 [1.02-1.44]), located 34 kb downstream of the P2 promoter. Meta-analysis, comprising 12,292 type 2 diabetic case and 15,519 control subjects, revealed a nonsignificant OR of 1.05 (95% CI 0.98-1.12) but with significant heterogeneity between the populations. We therefore performed a subanalysis including only the data for subjects from Scandinavia. Among the 4,000 case and 7,571 control Scandinavian subjects, a pooled OR of 1.14 (1.06-1.23), P = 0.0004, was found for the SNP rs1884613.
  
  
  CONCLUSIONS
  Our results suggest that variation in the HNF4A region is associated with type 2 diabetes in Scandinavians, highlighting the importance of exploring small genetic effects in large, homogenous populations.
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.forename: Helge
authors.initials: H
authors.lastname: Raeder
authors.forename: Stig A
authors.initials: SA
authors.lastname: Eide
authors.forename: Kristian
authors.initials: K
authors.lastname: Midthjell
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.forename: Oddmund
authors.initials: O
authors.lastname: Søvik
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
authors.forename: Pål Rasmus
authors.initials: PR
authors.lastname: Njølstad
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009664:Norway / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012016:Reference Values; D012537:Scandinavian and Nordic Countries / Q000453:epidemiology; D044465:White People