Assessment of the non-HLA-DR-DQ contribution to IDDM1 in British Caucasian families:: analysis of LMP7 polymorphisms

Aims Whilst HLA-DRB1 and HLA-DQ alleles contribute to IDDM1, the major determinant of genetic susceptibility to Type 1 diabetes mellitus, other major histocompatibility complex (MHC)-encoded genes may also be involved. The LMP7 (large multifunctional proteasome 7) gene is a potential candidate. The aim of this study was to assess whether LMP7 confers susceptibility to Type 1 diabetes independently of linkage disequilibrium with HLA-DRB1 and HLA-DQ. Methods The diallelic LMP7 polymorphism (LMP7*A or *B) was determined in 142 multiplex families from the British Diabetic Association Warren Repository. At least one parent was heterozygous for LMP7 in 112 families and these were informative for calculation of the statistic T-sp. This gives a valid chi (2) test of the null hypothesis of no association or no linkage. Results An excess of transmissions of LMP7*A was observed from parents to affected offspring and the T-sp statistic was significant for association in the presence of linkage, LMP7*A was in positive, and LMP7*B in negative, linkage disequilibrium with the HLA-DRB1*03-DQ2, DRB1*04-DQ8 (group of all DRB1*04 subtypes), DRB1*0401-DQ8 and DRB1*0404-DQ8 haplotypes, although the linkage disequilibrium coefficient (Delta) value was not statistically significant for DRB1*0404-DQ8. Analysis of HLA-DR-DQ- LMP7 haplotypes and T-sp analysis of HLA-matched-homozygous parents showed no association between LMP7 alleles and Type I diabetes independent of linkage disequilibrium with HLA-DR-DQ haplotypes associated with increased risk of disease. A contribution of LMP7 alleles to susceptibility to Type 1 diabetes in subjects with low-risk HLA-DR-DQ haplotypes could not be excluded. Conclusions LMP7 alleles do not contribute to genetic susceptibility to Type 1 diabetes in subjects with high-risk-associated HLA-DR-DQ haplotypes.