title: High-density haplotype structure and association testing of the insulin-degrading enzyme (IDE) gene with type 2 diabetes in 4,206 people.
abstract: 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 single-marker 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.
authors.affiliation: Diabetes Unit, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. jcflorez@partners.org
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Steven
authors.initials: S
authors.lastname: Wiltshire
authors.forename: Christina M
authors.initials: CM
authors.lastname: Agapakis
authors.forename: Noël P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Kristina
authors.initials: K
authors.lastname: Bengtsson Boström
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007339:Insulysin / Q000235:genetics*; D015810:Linkage Disequilibrium; D010641:Phenotype; D044465:White People
chemical_list: D007339:Insulysin