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

Abstract

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 ¼ 0.16 for rs7923837 and 64.6 vs 60.4%, P ¼ 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 ¼ 0.017 and rs1111875: OR: 1.68, 95% CI: 1.19 -2.35, P ¼ 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.

Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese

“…22,23,30,31 On the other hand, the association study and meta-analysis further confirmed the effect of HHEX rs1111875 on type 2 diabetes in Chinese population, consistent with previous genome-wide association studies and replication studies in other ethnic populations. [15][16][17][18][19]25,26,[32][33][34] The HHEX gene encodes a transcription factor that is also involved in the Wnt signaling pathway and that has been shown to be essential for pancreas development. van Vliet-Ostaptchouk et al 19 suggested that HHEX was the most likely causal candidate in chromosome 10q.…”

“…[15][16][17][18][19]25,26,[32][33][34] The HHEX gene encodes a transcription factor that is also involved in the Wnt signaling pathway and that has been shown to be essential for pancreas development. van Vliet-Ostaptchouk et al 19 suggested that HHEX was the most likely causal candidate in chromosome 10q. However, in our study, both IDE rs11187007 and HHEX rs1111875 were detected to be associated with type 2 diabetes.…”

“…14 Both HHEX and IDE genes have strong biological claims for a role in type 2 diabetes pathogenesis. However, all significant variants of this locus identified by genome-wide association studies of different ethnic groups were all located in 3¢ region of HHEX gene, [15][16][17][18] therefore, some studies suggested that HHEX was the most likely causal candidate gene for type 2 diabetes in chromosome 10q23-q25 19 and paid much attention to the HHEX gene. Here, eight common tag-SNPs, which covered both HHEX and IDE genes, were genotyped to analyze their effects on type 2 diabetes.…”

Association between single nucleotide polymorphisms in CDKAL1 and HHEX and type 2 diabetes in Chinese Population

“…In 2007, the rs1111875C in the HHEX gene was reported to be associated with T2DM in Finland and Sweden populations [18]. In 2008, Jana et al [35] conducted an association study, their data con rmed the association of the common variant rs1111875C in the HHEX gene, identi ed by Sladek et al [36] in French population, with an increased risk of T2DM in a Dutch population. In 2008, Wu et al reported that the associations of the HHEX rs1111875C allele with T2DM in Chinese Shanghai population [14].…”

Genetic Variants of IDE-KIF11-HHEX at 10q23.33 Associated with Type 2 Diabetes Risk: A Fine-Mapping Study in Chinese Population

“…Several studies also reported associations between rs1111875 and rs7923837 and fasting insulin secretion, insulin sensitivity and insulin secretion response following a glucose load [28]–[32]. Therefore, HHEX was suggested as the most likely causal candidate gene at 10q23.33 for type 2 diabetes [33]. Nevertheless, IDE is also another strong candidate gene.…”