This study was aimed to assess the association of the two single nucleotide polymorphisms (SNPs) near P2 promoter (rs1884614 and rs2144908) of hepatocyte nuclear factor-4alpha (HNF4A) with insulin secretion index and type 2 diabetes in Thais.
HNF1A is a gene coding for the transcription factor HNF1-α, mutated in some forms of MODY and type 2 diabetes mellitus characterized by a strong genetic component.
Considering a strong association between human HNF4A polymorphisms and increased risk of type 2 diabetes our current findings suggest that downregulation of AGXT2 and subsequent impairment in metabolism of dimethylarginines and BAIB caused by HNF4α deficiency might contribute to development of cardiovascular complications in diabetic patients.
In conclusion, subjects with HNF4 alpha P2 variants and haplotypes have been shown to have a higher insulin resistance and are therefore at a higher risk for developing type 2 diabetes mellitus.
This mutation was also identified in another proband from the autosomal dominant T2D family without mutation in known MODY genes and was segregated with diabetes.
Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha.
Our aim was to determine the prevalence of the most common MODY genes in Italian families with early-onset Type II (non-insulin-dependent) diabetes mellitus.
The maturity-onset diabetes of the young (MODY), an autosomal dominant form of non-insulin dependent diabetes mellitus (NIDDM), is caused by mutations in the glucokinase (GK, MODY 2) and in the hepatocyte nuclear factor 1a (MODY 3) and 4a (MODY 1) genes.
Finally, the example of single gene diabetes, particularly HNF1A MODY and permanent neonatal diabetes associated with the KCNJ11 and ABCC8 genes, all efficiently controlled on sulfonylurea, inspires us to continue the efforts to tailor individual treatment for T2DM patients.
Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes.
The study included 220 affected subjects from 29 families in which early-onset type 2 diabetes occurred in multiple generations and was not linked to known MODY genes (MODY gene-negative families).
We combined these results with our previous studies on HNF4alpha and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes.
During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age.
We recommend inclusion of exon 1E and nearby DNA sequences in screening for HNF4alpha mutations and polymorphisms in genetic analyses of MODY1 and T2DM.
Genetic analysis revealed a novel variant (p.Pro190Leu) in HNF4A, which is located in the ligand binding domain of the transcription factor, and the p.Glu23Lys variant in KCNJ11, which is associated with type 2 diabetes.
Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive.
The four polymorphisms, rs4810424, rs1884613, rs1884614 and rs2144908, in the HNF‑4α gene were not the susceptible loci for type 2 diabetes in the Bai population of Dali city, however, the haplotype, CCTA, built from the four SNPs may increase the risk of type 2 diabetes in this population.