Association of the large multifunctional proteasome (LMP2) gene with Graves' disease is a result of linkage disequilibrium with the HLA haplotype DRB1*0304-DQB1*O2-DQA1*0501

OBJECTIVE The large multifunctional proteasome (LMP) molecules are over exp ressed in thyrocytes, the target cells of Graves' disease, and the LMP gene s are found within the MHC class II region, The LMP genes may therefore pla y a role in susceptibility to Graves' disease. The aim of this this study w as to determine whether polymorphisms of the LMP genes, LMP 2 and LMP 7 are in linkage disequilibrium with Graves' disease. DESIGN Target DNA was amplified using the polymerase chain reaction. The di stribution of an Arg-His polymorphism in the LMP 2 gene and a GIT polymorph ism in the LMP 7 gene, both of which lead to the presence of an Hhal restri ction site, were investigated in a population based case control and family based study in patients with Graves' disease, PATIENTS We obtained DNA from 306 patients with Graves' disease and 364 con trol subjects for the population based case-control study. In an independen t family based study, DNA was obtained from 129 families including both par ents, an affected sibling with Graves' disease and an unaffected sibling. A ll families, patients and control subjects were white caucasians. MEASUREMENTS Frequencies of the alleles and genotypes of the LMP 2 and LMP 7 genes were compared between patients and control subjects using the chi(2 ) test, Transmission of alleles from heterozygous parents to affected and u naffected offspring was assessed using the transmission disequilibrium test (TDT), RESULTS In the case control study, no difference in allele or genotype freq uency was seen between patients and control subjects at the LMP7 locus, At the LMP2 locus the R allele and the RH genotype were increased in subjects with Graves' disease when compared with control subjects (R allele: 36.3% v s. 29.5%, pc = 0.0164; RH genotype: 56.5% vs. 45%, pc = 0.0102), However, t he R allele was in linkage disequilibrium with the associated HLA DRB1*0304 -DQB1*02-DQA1*0501 haplotype, delta = 0.102. Within the family based study, no preferential allelic transmission was seen from heterozygote parents to offspring at either loci. CONCLUSION These results show that association o f the LMP 2 locus with Graves' disease is due to linkage disequilibrium wit h the associated HLA haplotype DRB1*0304-DQB1*02-DQA1*0501.