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Susceptibility to, and protection against development of type 1 diabetes (T1D) are primarily associated with the highly polymorphic exon 2 sequences of the HLA class II genes: DQB1, DQA1 and DRB1. However, several studies have also suggested that additional genes in the HLA complex influence T1D risk, albeit to a lesser degree than the class II genes. We have previously shown that allele 3 of microsatellite marker D6S2223, 4.9 Mb telomeric of DQ in the extended class I region, is associated with a reduction in risk conferred by the DQ2-DR3 haplotype. Here we replicate this finding in two populations from Sweden and France. We also show that markers in the HLA class II, III and centromeric class I regions contribute to the DQ2-DR3 associated risk of T1D, independently of linkage disequilibrium (LD) with both the DQ/DR genes and the D6S2223 associated gene. The associated marker alleles are carried on the DQ2-DR3-B18 haplotype in a region of strong LD. By haplotype mapping, we have located the most likely location for this second DQ2-DR3 haplotype-modifying locus to the 2.35 Mb region between HLA-DOB and marker D6S2702, located 970 kb telomeric of HLA-B.

Original publication

DOI

10.1038/sj.gene.6363917

Type

Journal article

Journal

Genes Immun

Publication Date

01/2003

Volume

4

Pages

46 - 53

Keywords

Chi-Square Distribution, Confidence Intervals, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Genotype, HLA-DQ Antigens, HLA-DQ alpha-Chains, HLA-DQ beta-Chains, HLA-DR Antigens, HLA-DRB1 Chains, Haplotypes, Humans, Microsatellite Repeats, Odds Ratio