Background: The nuclear receptor hepatocyte nuclear factor 4alpha (HNF4alpha) contributes to the regulation of a large fraction of liver and pancreatic islet transcriptomes.
Aim: To evaluate the influence of HNF4alpha polymorphisms across the entire locus on the occurrence of type 2 diabetes (T2D) by means of a meta-analysis.
Methods: We evaluated haplotype block structure of HNF4alpha variants owing to linkage disequilibrium (LD). From 1455 reports, we evaluated 21 observational studies.
Results: Six haplotype blocks of LD were constructed with SNPs with r(2)>0.8; there were also 14 unlinked SNPs. Overall, we included 22,920 cases and 26.657 controls. Among 17 heterogeneous studies (21,881 cases and 24,915 controls), including 3 SNPs of P2 promoter region in block 1, we observed a significant association with T2D in fixed (OR 0.94, 95%CI: 0.905-0.975, p=0.001) and random (OR 0.988, 95%CI: 0.880-0.948, p=0.000012) model. Three homogeneous studies were evaluated in block 2 (2684 cases and 2059 controls), and a significant association with T2D was also observed: OR: 1.121, 95%CI 1.013-1.241, p=0.027. 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).
Conclusions: In addition to HNF4alpha variants in the promoter region, other SNPs may be involved on the occurrence of T2D.