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
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.