title: 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, -179T-->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, IVS20-405A-->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.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Site, Old Road, Headington, Oxford OX3 7LJ, U.K.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Groves
authors.forename: Steven
authors.initials: S
authors.lastname: Wiltshire
authors.forename: Damian
authors.initials: D
authors.lastname: Smedley
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Levy
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D022202:Chromosomes, Artificial, Bacterial; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006239:Haplotypes; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007339:Insulysin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D001786:Blood Glucose; D012333:RNA, Messenger; D007339:Insulysin; D005947:Glucose