1. ¹Institute of Immunology, Rikshospitalet University Hospital, Norway
2. ²JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, UK
3. ³Steno Diabetes Center, Gentofte, Denmark
4. ⁴Inserm U 558, Toulouse, France
5. ⁵Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

Correspondence: Dr S Johansson, Institute of Immunology, Rikshospitalet University Hospital, 0027 Oslo, Norway. E-mail: stefan.johansson@labmed.uio.no

⁶These authors contributed equally.

Abstract

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.