title: Remapping the insulin gene/IDDM2 locus in type 1 diabetes.
abstract: Type 1 diabetes susceptibility at the IDDM2 locus was previously mapped to a variable number tandem repeat (VNTR) 5' of the insulin gene (INS). However, the observation of associated markers outside a 4.1-kb interval, previously considered to define the limits of IDDM2 association, raised the possibility that the VNTR association might result from linkage disequilibrium (LD) with an unknown polymorphism. We therefore identified a total of 177 polymorphisms and obtained genotypes for 75 of these in up to 434 pedigrees. We found that, whereas disease susceptibility did map to within the 4.1-kb region, there were two equally likely candidates for the causal variant, -23HphI and +1140A/C, in addition to the VNTR. Further analyses in 2,960 pedigrees did not support the difference in association between VNTR lineages that had previously enabled the exclusion of these two polymorphisms. Therefore, we were unable to rule out -23HphI and +1140A/C having an etiological effect. Our mapping results using robust regression methods show how precisely a variant for a common disease can be mapped, even within a region of strong LD, and specifically that IDDM2 maps to one or more of three common variants in a approximately 2-kb region of chromosome 11p15.
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. bryan.barratt@cimr.cam.ac.uk
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Barratt
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.forename: Chris E
authors.initials: CE
authors.lastname: Lowe
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
authors.forename: Barry C
authors.initials: BC
authors.lastname: Healy
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.forename: Neda
authors.initials: N
authors.lastname: Gharani
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Mark G
authors.initials: MG
authors.lastname: Olavesen
authors.forename: Rose
authors.initials: R
authors.lastname: McCormack
authors.forename: Cristian
authors.initials: C
authors.lastname: Guja
authors.forename: Constantin
authors.initials: C
authors.lastname: Ionescu-Tîrgovişte
authors.forename: Dag E
authors.initials: DE
authors.lastname: Undlien
authors.forename: Kjersti S
authors.initials: KS
authors.lastname: Rønningen
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillespie
authors.forename: Eva
authors.initials: E
authors.lastname: Tuomilehto-Wolf
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Simon T
authors.initials: ST
authors.lastname: Bennett
authors.forename: David G
authors.initials: DG
authors.lastname: Clayton
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics*; D018598:Minisatellite Repeats; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic
chemical_list: D007328:Insulin