The insulin-degrading enzyme is responsible for the intracellular proteolysis of insulin. Its gene IDE is located on chromosome 10, in an area with suggestive linkage to type 2 diabetes and related phenotypes. Due to the impact of genetic variants of this gene in rodents and the function of its protein product, it has been proposed as a candidate gene for type 2 diabetes. Various groups have explored the role of the common genetic variation of IDE on insulin resistance and reported associations of various single nucleotide polymorphisms (SNPs) and haplotypes on both type 2 diabetes and glycemic traits. We sought to characterize the haplotype structure of IDE in detail and replicate the association of common variants with type 2 diabetes, fasting insulin, fasting glucose, and insulin resistance. We assessed linkage disequilibrium, selected singlemarker and multimarker tags, and genotyped these markers in several case-control and family-based samples totalling 4,206 Caucasian individuals. We observed no statistically significant evidence of association between single-marker or multimarker tests in IDE and type 2 diabetes. Nominally significant differences in quantitative traits are consistent with statistical noise. We conclude that common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians. T he insulin-degrading enzyme (IDE or insulysin, EC 3.4.24.56) is a ϳ110-kDa member of the M16 family of zinc-metalloendopeptidases involved in the proteolysis of various amyloidogenic peptides such as insulin, glucagon, amyloid ␤-protein, amylin, and atrial natriuretic protein (rev. in 1). Due to its role in intracellular insulin degradation, it has been postulated as a possible contributor to insulin resistance in humans.Several lines of evidence implicate the IDE gene in the pathogenesis of type 2 diabetes. First, IDE activity is reduced by 30% in the diabetic Goto-Kakizaki rat model, and two amino acid substitutions in the Ide gene have been shown to be responsible for postprandial hyperglycemia in congenic strains (2). Second, Ide-null mice display hyperinsulinemia and glucose intolerance (3). Third, the human IDE gene is located on chromosome 10q23-24, within 4 -30 Mb from markers that have shown suggestive linkage for type 2 diabetes and related phenotypes in a number of whole-genome linkage studies (4 -7). Fourth, several association studies have reported nominal association of IDE single nucleotide polymorphisms (SNPs) or haplotypes with type 2 diabetes and/or glycemic traits (8 -10).In type 2 diabetes, robust reproducible associations continue to be documented for the P12A polymorphism in the peroxisome proliferator-activated receptor ␥ (encoded by PPARG) and the E23K polymorphism in KCNJ11, which encodes the ATP-sensitive K ϩ channel Kir6.2 (recently rev. in 11). We aim to provide similar levels of evidence for other intriguing reports of association in high-likelihood candidate genes; as previously noted (12), when adequately powered samples are studied, true ...