Abstract
BackgroundGenome-wide association studies (GWAS) in populations of European ancestry have mapped a type 2 diabetes susceptibility region to chromosome 10q23.33 containing IDE, KIF11 and HHEX genes (IDE-KIF11-HHEX), which has also been replicated in Chinese populations. However, the functional relevance for genetic variants at this locus is still unclear. It is critical to systematically assess the relationship of genetic variants in this region with the risk of type 2 diabetes.Methodology/Principal FindingsA fine-mapping study was conducted by genotyping fourteen tagging single-nucleotide polymorphisms (SNPs) in a 290-kb linkage disequilibrium (LD) region using a two-stage case-control study of type 2 diabetes in a Chinese Han population. Suggestive associations (P<0.05) observed from 1,200 cases and 1,200 controls in the first stage were further replicated in 1,725 cases and 2,081 controls in the second stage. Seven tagging SNPs were consistently associated with type 2 diabetes in both stages (P<0.05), with combined odds ratios (ORs) ranging from 1.14 to 1.33 in the combined analysis. The most significant locus was rs7923837 [OR = 1.33, 95% confidence interval (CI): 1.21–1.47] at the 3′-flanking region of HHEX gene. SNP rs1111875 was found to be another partially independent locus (OR = 1.23, 95% CI: 1.13–1.35) in this region that was associated with type 2 diabetes risk. A cumulative effect of rs7923837 and rs1111875 was observed with individuals carrying 1, 2, and 3 or 4 risk alleles having a 1.27, 1.44, and 1.73-fold increased risk, respectively, for type 2 diabetes (P for trend = 4.1E-10).Conclusions/SignificanceOur results confirm that genetic variants of the IDE-KIF11-HHEX region at 10q23.33 contribute to type 2 diabetes susceptibility and suggest that rs7923837 may represent the strongest signal related to type 2 diabetes risk in the Chinese Han population.
Highlights
Type 2 diabetes is one of major public health problems around the world with an affected number of 240 million in 2007, with an expected rapid increase to 380 million by 2025 [1]
The current study represents the first fine-mapping study with an effort to comprehensively investigate the relationship between insulin-degrading enzyme (IDE)-kinesininteracting factor 11 (KIF11)-hematopoietically expressed homeobox (HHEX) locus and type 2 diabetes risk in this Chinese population
We confirmed the associations of genetic variants at IDE-KIF11-HHEX gene region with risk of type 2 diabetes in Chinese Han population
Summary
Type 2 diabetes is one of major public health problems around the world with an affected number of 240 million in 2007, with an expected rapid increase to 380 million by 2025 [1]. In 2007, the first GWAS of type 2 diabetes conducted in a French case-control cohort identified a type 2 diabetes related locus on chromosome 10q23.33, which is located in a gene cluster including the insulin-degrading enzyme (IDE), the kinesininteracting factor 11 (KIF11), and the hematopoietically expressed homeobox (HHEX) [3] This association has been consistently replicated in the subsequent studies [4,5,6,7,8,9], including several studies in Chinese populations [10,11,12,13,14,15,16,17]. Reduction of IDE activity by a pharmacological inhibitor increases islet amyloid polypeptide (amylin) accumulation and amylin-mediated cytotoxicity in cultured b-cells [19], whereas IDE ablation causes glucose intolerance in knockout mice [20] Both IDE and HHEX genes are strong candidates as susceptibility genes modulating the pathogenesis of type 2 diabetes. It is critical to systematically assess the relationship of genetic variants in this region with the risk of type 2 diabetes
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