Cl. Mcternan et al., Assessment of the non-HLA-DR-DQ contribution to IDDM1 in British Caucasianfamilies: analysis of LMP7 polymorphisms, DIABET MED, 17(9), 2000, pp. 661-666
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.