HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort

Recently, the hematopoietically expressed homeobox ( HHEX) gene, encoding a transcription factor, was identified in a large genome-wide scan in French individuals as a type 2 diabetes ( T2D)-susceptibility locus. We aimed to check whether this finding could be replicated in a Dutch T2D cohort. Two common variants ( rs7923837 and rs1111875) located near the HHEX gene were genotyped in 501 unrelated T2D patients and in 920 healthy controls. The major alleles of both variants were overrepresented in T2D cases compared with controls ( 66.7 vs 64.1%, P = 0.16 for rs7923837 and 64.6 vs 60.4%, P = 0.027 for rs1111875). For both polymorphisms, the risk for T2D was significantly increased in carriers of the major alleles ( rs7923837: odds ratio ( OR): 1.57, 95% confidence interval ( CI): 1.08 - 2.27, P = 0.017 and rs1111875: OR: 1.68, 95% CI: 1.19 - 2.35, P = 0.003). The haplotype analysis did not reveal a risk haplotype that provided stronger evidence for association with T2D than each variant individually. Assuming a dominant genetic model, the population-attributable risks for diabetes due to the at- risk alleles of rs7923837 and rs1111875 were estimated to be 33 and 36%, respectively. These data provide evidence that variants near the HHEX gene contribute to the risk of T2D in a Dutch population.