Remapping the insulin gene/IDDM2 locus in type 1 diabetes.
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.
Barratt
Bryan J
BJ
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
Payne
Felicity
F
Lowe
Chris E
CE
Hermann
Robert
R
Healy
Barry C
BC
Harold
Denise
D
Concannon
Patrick
P
Gharani
Neda
N
McCarthy
Mark I
MI
Olavesen
Mark G
MG
McCormack
Rose
R
Guja
Cristian
C
Ionescu-Tîrgovişte
Constantin
C
Undlien
Dag E
DE
Rønningen
Kjersti S
KS
Gillespie
Kathleen M
KM
Tuomilehto-Wolf
Eva
E
Tuomilehto
Jaakko
J
Bennett
Simon T
ST
Clayton
David G
DG
Cordell
Heather J
HJ
Todd
John A
JA
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
D007328:Insulin