In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes in a collection of Caucasian type 2 diabetic patients with end-stage renal disease (n = 300) and control subjects (n = 310).
We report that the HMG20A (rs7178572) and HNF4A (rs4812829) variants that have previously shown a strong association with T2DM in Asian Indians also contributes significant risk to GDM in this population.
Linkage studies have been done in MODY families reported to have no mutations in the five known MODY genes and in affected sibling pairs from families with late-onset Type II diabetes.
However, positivity for ZnTA can be used as a negative MODY pre-diagnostic criterion even in the region of Central and East Europe, where other islet cell autoantibodies are common in MODY patients.
We screened PAX4 coding sequences in 46 MODY probands without mutation in known MODY genes and in 74 nondiabetic controls using PCR-single-stranded conformational polymorphism analysis followed by direct sequencing.
The results indicate that as in white patients, MODY resulting from mutations in the HNF-1 alpha, HNF-1 beta, and HNF-4 alpha genes in Japanese patients may be a severe disease similar to classic type 2 diabetes.
Furthermore, because KLF11 like most MODY-associated transcription factors uses p300, these data further support a role for this coactivator as a critical chromatin link in forms of type 2 diabetes.
The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the genes regulating insulin secretion (SLC2A2 [encoding GLUT2], GCK, TCF1 [encoding HNF-1alpha], HNF4A, GIP, and GLP1R) are associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in participants of the Finnish Diabetes Prevention Study.
Rare loss-of-function mutations in HNF4A cause maturity-onset diabetes of the young and now common noncoding variants have been found to be associated with T2DM.
Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
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.
To assess the role of the P2 region we screened MODY, young-onset Type II diabetic subjects, and probands from Type II diabetes families linked to chromosome 20 for variants of the P2 promoter and associated exon of HNF-4 alpha.
Considering a strong association between HNF4A deregulation and increased risk of T2DM, our findings suggest that HNF4α may act as a critical converging point linking hyperprocoagulant condition to VEGF resistance in diabetic ECs, and repression of FLK1 expression by thrombin-induced HNF4α mediates, at least partially, the vascular dysfunction caused by T2DM.
Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x 10(-6)).
Although the univariate association between the TCF7L2 SNP and T2D was relatively modest [P = 0.02], when paired with the HNF4A SNP, the OR for subjects with risk alleles in both SNPs was 2.4 [95% CI = 1.7-3.4; P<or=0.0001].
MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4 alpha) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) [MODY3].
In the discovery stage, an Asian-specific coding variant rs2233580 (p.Arg192His) in PAX4, and two variants at the known loci, CDKN2B-AS1 and KCNQ1, were significantly associated with type 2 diabetes with exome-wide significance (p <sub>discovery</sub> < 6.45 × 10<sup>-7</sup>).