P2 Promoter Variants of the Hepatocyte Nuclear Factor 4α Gene Are Associated With Type 2 Diabetes in Mexican Americans

Abstract

Common and rare variants of the hepatocyte nuclear factor 4␣ (HNF4A) gene have been associated with type 2 diabetes and related traits in several populations suggesting the involvement of this transcription factor in diabetes pathogenesis. Single nucleotide polymorphisms (SNPs) within a large haplotype block surrounding the alternate P2 promoter, located ϳ45 kb upstream from the coding region, have been investigated in several populations of varying ethnicity with inconsistent results. Additionally, SNPs located within the P1 promoter and coding region have also been inconsistently associated with type 2 diabetes. Characterization of variation across this gene region in Mexican-American populations has not been reported. We therefore examined polymorphisms across the HNF4A gene in a cohort of Mexican-American pedigrees and assessed their association with type 2 diabetes. We observed evidence for association of SNPs in the P2 promoter region with type 2 diabetes (P ‫؍‬ 0.003) and its age at diagnosis (P ‫؍‬ 0.003). The risk allele frequency (53%) was intermediate to that reported in Caucasian populations (20 -27%) and Pima Indians (83%). No other SNPs were associated with either trait. These results support the possibility that a variant in the P2 promoter region of HNF4A, or variants in linkage disequilibrium within this region, contributes to susceptibility to type 2 diabetes in many ethnic populations including Mexican Americans. Diabetes 56:513-517, 2007

Prediabetes Is Associated withHNF-4αP2 Promoter Polymorphism rs1884613: A Case-Control Study in Han Chinese Population and an Updated Meta-Analysis

“…Consistent with our study, Winckler et al and Bagwell et al reported no association of HNF-4α polymorphisms (including rs1884613) with T2D in Scandinavians and Caucasian Americans [11, 18], although several other studies found the significant association with risk of T2D in the Finnish population [16], the Ashkenazi Jews [15], the Mexican Americans [21], and the Norwegians [17]. The opposite findings among different studies may be due to different sample size, environmental factors, and different genetic backgrounds.…”

Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in Type 2 Diabetes in a Chinese population

“…However, we observed an association between WFS1 -rs6446482 with T2D in our meta-analysis, and early-onset T2D in our own sample. Wolfram syndrome, characterized by early-onset diabetes, optic atrophy, deafness, and diabetes insipidus is due to mutations of the WFS1 gene [34], which regulates ί cell function in mice [35] and glucagon-like peptide 1-induced insulin secretion in humans [36], suggesting that impaired beta cell function in subjects with the risk allele of WFS1 may promote the onset of T2D as seen in other monogenetic diabetes [37,38]. Thus, it is necessary to replicate this study in a larger sample and sequence this gene for real causative variants.…”

Down-Regulation of Hepatic HNF4α Gene Expression during Hyperinsulinemia via SREBPs

“…The effect of the MODY1 mutations are presumably on the pancreatic form of HNF4␣ because single-nucleotide polymorphisms in the P2 promoter that drives ␤-cell expression have also been linked to MODY1 (see Ref. 8 and references therein); no such mutations have been identified in the P1 promoter that drives expression in the liver. Consequently, several studies have investigated the role of pancreatic HNF4␣ in diabetes (5,9,10), but much less is known about the role of hepatic HNF4␣ in diabetes.…”