Association of the large multifunctional proteasome (LMP2) gene with Graves' disease is a result of linkage disequilibrium with the HLA haplotype DRB1*0304-DQB1*02-DQA1*0501

Autor: Michael C. Sheppard, J. M. Heward, A. Allahabadia, A. H. Barnett, Jayne Franklyn, S. C. L. Gough
Rok vydání: 1999
Předmět:
Zdroj: Clinical Endocrinology. 51:115-118
ISSN: 0300-0664
DOI: 10.1046/j.1365-2265.1999.00755.x
Popis: OBJECTIVE The large multifunctional proteasome (LMP) molecules are over expressed in thyrocytes, the target cells of Graves' disease, and the LMP genes are found within the MHC class II region. The LMP genes may therefore play a role in susceptibility to Graves' disease. The aim of this this study was 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 distribution of an Arg-His polymorphism in the LMP2 gene and a G/T polymorphism in the LMP 7 gene, both of which lead to the presence of an HhaI restriction 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 control subjects for the population based case-control study. In an independent family based study, DNA was obtained from 129 families including both parents, an affected sibling with Graves' disease and an unaffected sibling. All 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 χ2 test. Transmission of alleles from heterozygous parents to affected and unaffected offspring was assessed using the transmission disequilibrium test (TDT). RESULTS In the case control study, no difference in allele or genotype frequency 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% vs. 29.5%, pc = 0.0164; RH genotype: 56.5% vs. 45%, pc = 0.0102). However, the R allele was in linkage disequilibrium with the associated HLA DRB1*0304-DQB1*02-DQA1*0501 haplotype, δ = 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 of the LMP 2 locus with Graves' disease is due to linkage disequilibrium with the associated HLA haplotype DRB1*0304-DQB1*02-DQA1*0501.
Databáze: OpenAIRE
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