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Remapping the insulin gene/IDDM2 locus in type 1 diabetes
Bryan J Barratt1, Felicity Payne, Chris E Lowe
1Juvenile 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
Diabetes
|June 29, 2004
Summary
Researchers pinpointed the genetic cause of Type 1 diabetes (T1D) susceptibility at the IDDM2 locus. The study identified three potential causal variants within a 2-kb region of chromosome 11p15, refining our understanding of T1D genetics.
Area of Science:
- Genetics
- Immunology
- Endocrinology
Background:
- Type 1 diabetes (T1D) susceptibility has been linked to the IDDM2 locus, specifically a variable number tandem repeat (VNTR) upstream of the insulin gene (INS).
- Previous studies defined the IDDM2 association to a 4.1-kb interval, but associated markers outside this region suggested potential linkage disequilibrium (LD) with unidentified polymorphisms.
Purpose of the Study:
- To precisely map the causal variant(s) responsible for T1D susceptibility at the IDDM2 locus.
- To investigate the role of novel polymorphisms in T1D pathogenesis, beyond the previously identified VNTR.
Main Methods:
- Identification and genotyping of 177 polymorphisms in up to 434 pedigrees.
- Utilized robust regression methods for precise genetic mapping within a region of strong LD.
- Performed further analyses in 2,960 pedigrees to re-evaluate associations.
Main Results:
- Disease susceptibility was confirmed to map within the 4.1-kb region.
- Identified three equally likely candidate causal variants: the VNTR, -23HphI, and +1140A/C.
- Subsequent analyses in a larger cohort could not exclude -23HphI and +1140A/C as etiological factors.
Conclusions:
- The IDDM2 locus, associated with T1D susceptibility, maps to a ~2-kb region on chromosome 11p15.
- One or more of three common variants (VNTR, -23HphI, +1140A/C) likely contribute to T1D pathogenesis.
- This study demonstrates precise mapping of common disease variants even within regions of strong LD.