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

Aims Whilst HLA-DRB1 and HLA-DQ alleles contribute to IDDM1, the major dete rminant of genetic susceptibility to Type 1 diabetes mellitus, other major histocompatibility complex (MHC)-encoded genes may also be involved. The LM P7 (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-D Q. Methods The diallelic LMP7 polymorphism (LMP7*A or *B) was determined in 14 2 multiplex families from the British Diabetic Association Warren Repositor y. 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 a ffected 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, l inkage disequilibrium with the HLA-DRB1*03-DQ2, DRB1*04-DQ8 (group of all D RB1*04 subtypes), DRB1*0401-DQ8 and DRB1*0404-DQ8 haplotypes, although the linkage disequilibrium coefficient (Delta) value was not statistically sign ificant for DRB1*0404-DQ8. Analysis of HLA-DR-DQ- LMP7 haplotypes and T-sp analysis of HLA-matched-homozygous parents showed no association between LM P7 alleles and Type I diabetes independent of linkage disequilibrium with H LA-DR-DQ haplotypes associated with increased risk of disease. A contributi on of LMP7 alleles to susceptibility to Type 1 diabetes in subjects with lo w-risk HLA-DR-DQ haplotypes could not be excluded. Conclusions LMP7 alleles do not contribute to genetic susceptibility to Typ e 1 diabetes in subjects with high-risk-associated HLA-DR-DQ haplotypes.