Influence of hepatocyte nuclear factor 4alpha (HNF4alpha) gene variants on the risk of type 2 diabetes: a meta-analysis in 49,577 individuals.
BACKGROUND
The nuclear receptor hepatocyte nuclear factor 4alpha (HNF4alpha) contributes to the regulation of a large fraction of liver and pancreatic islet transcriptomes.


OBJECTIVE
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.
Sookoian
Silvia
S
Molecular Genetics and Biology of Complex Diseases Department, Institute of Medical Research A. Lanari, University of Buenos Aires--National Council of Scientific and Technological Research, Combatientes de Malvinas 3150, Buenos Aires (1427), Argentina.
Gemma
Carolina
C
Pirola
Carlos J
CJ
D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors
D051557:Hepatocyte Nuclear Factor 4