Examination of Rare Variants in HNF4α in European Americans with Type 2 Diabetes
- Corresponding Author:
- Donald W. Bowden, PhD
Department of Biochemistry
Wake Forest School of Medicine
Medical Center Blvd., Winston-Salem, NC 27157, USA
E-mail: [email protected]
Received Date: August 15, 2011; Accepted Date: September 10, 2011; Published Date: October 20, 2011
Citation: Hellwege JN, Hicks PJ, Palmer ND, Ng MCY, Freedman BI, et al. (2011) Examination of Rare Variants in HNF4a in European Americans with Type 2 Diabetes. J Diabetes Metab 2:145. doi:10.4172/2155-6156.1000145
Copyright: © 2011 Hellwege JN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The hepatocyte nuclear factor 4-α (HNF4 α ) gene codes for a transcription factor which is responsible for regulating gene transcription in pancreatic beta cells, in addition to its primary role in hepatic gene regulation. Mutations in this gene can lead to maturity-onset diabetes of the young (MODY), an uncommon, autosomal dominant, non-insulin dependent form of diabetes. Mutations in HNF4 α have been found in few individuals, and infrequently have they segregated completely with MODY in families. In addition, due to similarity of phenotypes, it is unclear what proportion of type 2 diabetes (T2DM) in the general population is due to MODY or HNF4 α mutations specifically. In this study, 27 documented rare and common variants were genotyped in a European American population of 1270 T2DM cases and 1017 controls from review of databases and literature implicating HNF4 α variants in MODY and T2DM. Seventeen variants were found to be monomorphic. Two cases and one control subject had one copy of a 6-bp P2 promoter deletion. The intron 1 variant (rs6103716; MAF = 0.31) was not significantly associated with disease status (p>0.8) and the missense variant Thr130Ile (rs1800961; MAF = 0.027) was also not significantly different between cases and controls (p>0.2), but showed a trend consistent with association with T2DM. Four variants were found to be rare as heterozygotes in small numbers of subjects. Since many variants were infrequent, a pooled chi-squared analysis of rare variants was used to assess the overall burden of variants between cases and controls. This analysis revealed no significant difference (P=0.22). We conclude there is little evidence to suggest that HNF4 α variants contribute significantly to risk of T2DM in the general population, but a modest contribution cannot be excluded. In addition, the observation of some mutations in controls suggests they are not highly penetrant MODY-causing variants.