Quantitative assessment of the influence of hematopoietically expressed homeobox variant (rs1111875) on type 2 diabetes risk

Hematopoietically expressed homeobox (HHEX) gene encodes for a transcription factor involved in Wnt/β-catenin signaling pathway which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) since it was first identified through genome wide association approach. The relationship between HHEX and T2D has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 26 studies involving a total of 110,875 subjects for rs1111875 of the HHEX gene to evaluate the effect of HHEX on genetic susceptibility for T2D. An overall random effects odds ratio of 1.16 (95% CI: 1.13–1.20) was found for C allele versus T allele. Significant results were also observed using dominant (OR = 1.21, 95% CI: 1.16–1.25) or recessive genetic model (OR = 1.24, 95% CI: 1.18–1.30). There was strong evidence of heterogeneity (P < 0.001), which largely disappeared after stratification by ethnicity. In the subgroup analysis by sample size, source of controls and diagnostic criterion, significantly increased risks were found for the polymorphism in all genetic models. This meta-analysis demonstrated that the C allele of rs1111875 of HHEX is a risk factor associated with increased T2D susceptibility, but these associations vary in different ethnic populations.