Among these nine SNPs that previously showed an association with T2DM in Asian Indians, HMG20A (rs7178572) and HNF4A (rs4812829</span>) gene variants showed a significant association with GDM.
The aim of the current study was to analyze the effect of six type II diabetes GWAS loci rs3923113 (GRB14), rs16861329 (ST6GAL1), rs1802295 (VPS26A), rs7178572 (HMG20A), rs2028299 (AP3S2) and rs4812829 (HNF4A), and an FTO polymorphism (rs9939609) on obesity.
We genotyped 11,319 Japanese participants (8,318 with type 2 diabetes and 3,001 controls) for each of the 7 SNPs-rs5945326 near DUSP9, rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, rs2028299 near AP3S2, and rs4812829 in HNF4A-and examined the association of each of these 7 SNPs with type 2 diabetes by using logistic regression analysis.
Thus, we aimed to investigate the contribution of rs1111875 (HHEX), rs1800961 (HNF4α), rs5219 (KCNJ11), rs1801282 (PPARγ), rs10811661 (CDKN2A/2B), rs13266634 (SLC30A8), rs12779790 (CDC123/CAMK1D), rs7903146 (TCF7L2), rs9282541 (ABCA1) and rs13342692 (SLC16A11) polymorphisms in the genetic background of Maya population to associate their susceptibility to develop T2D.
Three additional variants were associated with T2D: two intronic SNPs (rs4810424: OR: 1.080, 95%CI: 1.010-1.154, p<0.03 and rs3212183: OR: 0.843, 95%CI: 0.774-0.918, p<0.00009) and one missense variant (rs1800961: OR: 0.770, 95%CI: 0.595-0.995, p<0.05, 6562 cases and 6723 controls).
Meta-analysis showed only rs266729 and rs17300539 of ADIP</span>OQ, and rs1884613, rs2144908, and rs4810424 of HNF4A were significantly associated with T2D risk.
However, the frequency of haplotype, CCTA, built by rs4810424, rs1884613, rs1884614 and rs2144908 was significantly higher in the type 2 diabetes mellitus group compared with the control group (χ2=8.34, P=0.004).
The SNPs rs4810424, rs1884613, and rs2144908 were associated with protection against type 2 diabetes without metabolic syndrome (recessive P = 0.018, OR 0.32; P = 0.004, OR 0.25; P = 0.005, OR 0.24, respectively).
HNF4A promoter P2 polymorphisms rs1884613 and rs2144908, which are in high linkage disequilibrium, showed significant association with type 2 diabetes (odds ratio (OR)=1.37 (95% confidence interval (CI) 1.19-1.57), P=9.4 × 10(-6) for rs1884613 and OR=1.37 (95%CI 1.20-1.57), P=6.0 × 10(-6) for rs2144908), as previously shown in other populations.
The frequency of the minor allele of the rs2144908 was significantly higher in subjects with MODY (p < 0.01) and that of rs736823 was significantly higher in early onset T2DM (p = 0.001).
Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin (P = 0.004 under an additive model for rs2144908; and P = 0.001 under a dominant model for rs2144908) after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala.
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)).
In the Japanese population, a haplotype consisting of two SNPs (rs1884614 and rs2144908) in the P2 promoter region is reported to show a significant association with type 2 diabetes.
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.
The frequencies of the minor alleles were as follows: 19.2% in T2DM vs. 17.6% in controls for rs2144908; and 20.6% vs. 20.1% for rs4810424, respectively.
These results strongly suggest that the high frequency of the T130I polymorphism and its biological relationship with dysfunction in lipid metabolism in Mexican indigenous groups is a risk factor for the developing of T2D in Mexicans.
Mutation p.T130I was associated with both early-onset and late-onset diabetes and caused downregulated HNF4A expression, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with the age of diagnosis of diabetes.
Previous studies in the Mexican population have shown a high frequency of the Thr130Ile polymorphism and have suggested its important role in the pathogenesis of early-onset type 2 diabetes.
Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance.
In conclusion, The Thr130Ile and the Val255Met polymorphisms decrease the transcriptional activity of HNF4A, and the Thr130Ile polymorphism associates with T2D, whereas the Val255Met variant associates with a decrease in fasting serum C-peptide.
In the case-control analysis, PPARG rs1801282 (Pro12Ala) (OR=1.48 (1.02-2.16)), ADIPOQ rs1063539 (OR=1.17 (1.01-1.35)), and HNF4A rs1884614 (OR=1.16 (1.00-1.32) were associated with T2D (P(allelic)<0.05).
Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin (P = 0.004 under an additive model for rs2144908; and P = 0.001 under a dominant model for rs2144908) after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala.