Influence of hepatocyte nuclear factor 4α (HNF4α) gene variants on the risk of type 2 diabetes: a meta-analysis in 49,577 individuals

Abstract

BACKGROUND: The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) contributes to the regulation of a large fraction of liver and pancreatic islet transcriptomes. AIM: To evaluate the influence of HNF4α 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 HNF4α 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 r2 > 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 HNF4α variants in the promoter region, other SNPs may be involved on the occurrence of T2D.