Non-coding SNPs Near and Within the Hepatocyte Nuclear Factor-4 Alpha Gene are Associated with Type 2 Diabetes in Finns
L . J. Scott,1 K.L. Mohlke,2 K. Silander,3 E.C. Peck,2 P.E. Hollstein,2 A.D. Skol,1 P.S. Chines,2 T.T. Valle,3 R.N. Bergman,4 J. Tuomilehto,3 R.M. Watanabe, 4 F.S. Collins,2 M. Boehnke,1
Linkage to type 2 diabetes (T2D) on chromosome 20q13 has been observed in the Finland-United States Investigation of NIDDM genetics (FUSION) sample and other samples. Using a DNA pool-based approach followed by fine mapping in this region, we identified T2D associated SNPs near and within the Hepatocyte Nuclear Factor-4 Alpha (HNF4A) gene. Four associated SNPs located in the alternative transcription site P2 region are in almost perfect linkage disequilibrium (LD) and have frequencies of .21 in 767 cases and .16 in 398 controls (rs2144908, OR=1.33, p=.011). The rs2144908 risk allele was associated with lower acute insulin response to glucose (p=.003) and disposition index (p=.009) in 471 unaffected offspring of cases, suggesting this, or a variant in LD with it, may cause reduced pancreatic beta-cell function. Additional associated SNPs include a SNP between the P1 and P2 promoters with a frequency of .75 in cases and .69 in controls (OR=1.37, p=.002) and intronic SNPs located up to 54 kb further downstream. A haplotype comprised of the risk alleles of the 7 non-redundant associated SNPs showed an increased risk, but had a low frequency (.015 cases vs. .008 controls, OR=1.96, p=.056), suggesting that a single risk haplotype may not underlie all the observed associations. SNP rs2144908 and SNPs in almost perfect LD, were the only SNPs to partition the linkage signal, with LOD=1.86 vs. 0.28 for families in which a single genotyped individual had ≥ 1 vs. 0 copies of the risk allele. However we had limited power to test SNPs with higher risk allele frequencies. Love-Gregory et al. independently identified the same associated P2 SNPs in an Ashkenazi Jewish population. Variants in HNF4A are known to cause maturity-onset diabetes of the young (MODY). These data suggest that variants within HNF4A may also increase susceptibility to T2D.