Association and Haplotype Analysis of the Insulin-Degrading Enzyme (IDE) Gene, a Strong Positional and Biological Candidate for Type 2 Diabetes Susceptibility

Abstract

The gene for insulin-degrading enzyme (IDE) represents a strong positional and biological candidate for type 2 diabetes susceptibility. IDE maps to chromosome 10q23.3, a region linked to diabetes in several populations; the rat homolog has been directly implicated in diabetes susceptibility; and known functions of IDE support an important role in glucose homeostasis. We sought evidence for association between IDE variation and diabetes by mutation screening, defining local haplotype structure, and genotyping variants delineating common haplotypic diversity. An initial case-control analysis (628 diabetic probands from multiplex sibships and 604 control subjects) found no haplotypic associations, although one variant (IDE2, ؊179T3 C) showed modest association with diabetes (odds ratio [OR]1.25, P ‫؍‬ 0.03). Linkage partitioning analyses failed to support this association, but provided borderline evidence for a different variant (IDE10, IVS20 -405A3 G) (P ‫؍‬ 0.06). Neither variant was associated with diabetes when replication was sought in 377 early onset diabetic subjects and 825 control subjects, though combined analysis of all typed cohorts indicated a nominally significant effect at IDE2 (OR 1.21 [1.04 -1.40], P ‫؍‬ 0.013). In the absence of convincing support for this association from linkage partitioning or analyses of continuous measures of glycemia, we conclude that analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans.

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

“…30 Here, we found a novel association of rs11187007 with type 2 diabetes and triglycerides, in line with the findings that variants and haplotypes in IDE were associated with FPG, HbA1c and type 2 diabetes. 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.…”

“…For the HHEX-IDE locus, only representative SNPs with r 2 o0.80 based on HapMap Han Chinese were selected for genotyping, and eight variants (rs1111875, rs2275729, rs5015480, rs7923837, rs1887922, rs2209772, rs1999763 and rs11187007) which had positive association with type 2 diabetes or diabetes-related traits in previous studies were selected. [15][16][17][18][22][23][24][25][26] Genotyping All 13 variants were genotyped using TaqMan genotyping assay on an ABI7900 system (Applied Biosystems, Foster City, CA, USA). Genotyping success rates were above 95% except rs12779790 and all mismatch rates were below 1% in duplicate samples.…”

High-Density Haplotype Structure and Association Testing of the Insulin-Degrading Enzyme (IDE) Gene With Type 2 Diabetes in 4,206 People

“…Association study. To estimate the sample size required to replicate the main single-SNP association with type 2 diabetes of Groves et al (8) (SNP rs4646953), we assumed a minor allele frequency of 23%, a type 2 diabetes disease prevalence of 8%, and a genotypic relative risk of 1.2 in a multiplicative model. Under these parameters, we estimated that our combined sample of 1,112 case-control pairs would provide Ͼ80% power to reject the null hypothesis of no association at P Ͻ 0.05; this power is further raised by the inclusion of the family-based samples.…”

Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus

“…Written informed consent was obtained from each patient, and DNA extraction was performed using a standard phenol-chloroform procedure. The UK samples comprised 590 cases with type 2 diabetes enriched for positive family history (probands from the Diabetes UK Warren 2 repository) (Wiltshire et al 2001) and 549 UK population controls (the ECACC-HRC collection) (Groves et al 2003).…”