Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population

Abstract

Aims/hypothesis: Recently, several groups have carried out whole-genome association studies in European and European-origin populations and found novel type 2 diabetes-susceptibility genes, fat mass and obesity associated (FTO), solute carrier family 30 (zinc transporter), member 8 (SLC30A8), haematopoietically expressed homeobox (HHEX), exostoses (multiple) 2 (EXT2), CDK5 regulatory subunit associated protein 1-like 1 (CDKAL1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which had not been in the list of functional candidates. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) in these genes and type 2 diabetes in participants from the Japanese population. Methods: Sixteen previously reported SNPs were genotyped in 864 Japanese type 2 diabetes individuals (535 men and 329 women; age 63.1±9.5 years (mean±SD), BMI 24.3±3.9 kg/m2) and 864 Japanese control individuals (386 men and 478 women; age 69.5±6.8 years, BMI 23.8±3.7 kg/m 2). Results: The SNPs rs5015480 [odds ratio (OR)=1.46 (95% CI 1.20-1.77), p=2.0×10-4], rs7923837 [OR=1.40 (95% CI 1.17-1.68), p=2.0×10-4] and rs1111875 [OR=1.30 (95% CI 1.11-1.52), p=0.0013] in HHEX were significantly associated with type 2 diabetes with the same direction as previously reported. SNP rs8050136 in FTO was nominally associated with type 2 diabetes [OR=1.22 (95% CI 1.03-1.46), p=0.025]. SNPs in other genes such as rs7756992 in CDKAL1, rs10811661 in CDKN2B and rs13266634 in SLC30A8 showed nominal association with type 2 diabetes. rs7756992 in CDKAL1 and rs10811661 in CDKN2B were correlated with impaired pancreatic beta cell function as estimated by the homeostasis model assessment beta index (p=0.023, p=0.0083, respectively). Conclusions/interpretation: HHEX is a common type 2 diabetes-susceptibility gene across different ethnic groups. © 2007 Springer-Verlag.