Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and -DRB1

• Published in: Genes and immunity Vol. 4; no. 1; pp. 46 - 53
• Main Authors: JOHANSSON, S, LIE, B. A, TODD, J. A, POCIOT, F, NERUP, J, CAMBON-THOMSEN, A, KOCKUM, I, AKSELSEN, H. E, THORSBY, E, UNDLIEN, D. E
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.01.2003
• Subjects: Alleles; Analysis; Biological and medical sciences; Chi-Square Distribution; Confidence Intervals; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; DQA1 protein; Drb1 protein; Environmental impact analysis; Fundamental and applied biological sciences. Psychology; Gene expression; Genetic aspects; Genetic markers; Genetic Predisposition to Disease - genetics; Genotype; Haplotypes; Haplotypes - genetics; Health aspects; Histocompatibility antigen HLA; Histocompatibility antigens; HLA histocompatibility antigens; HLA-DQ alpha-Chains; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains; HLA-DR Antigens - genetics; HLA-DRB1 Chains; Humans; Linkage disequilibrium; Medicin och hälsovetenskap; Microbiology; Microsatellite Repeats - genetics; Microsatellites; Odds Ratio; Type 1 diabetes; Norway; Microbiology
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/sj.gene.6363917

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.