title: Compound heterozygosity for the shared epitope and the risk and severity of rheumatoid arthritis in extended pedigrees.
abstract: The objective was to explore the role of HLA-DRB1 genes in determining disease severity in rheumatoid arthritis (RA). The population comprised extended pedigrees of 17 multicase RA families. Family members were genotyped for both HLA-DRB1 alleles using restriction fragment length polymorphism (RFLP). Identification of HLA-DRB1*04 variants was performed using the Multiplex ARMS-RFLP technique. Compound heterozygote individuals carrying two different alleles containing the shared epitope (SE) were at greatest risk of developing RA (odds ratio = 36, 95% CI 9.1-143). A synergistic or additive effect of these alleles is suggested. Individuals carrying no SE alleles expressed milder disease, as measured by the Spread Severity (SS) index, compared to compound heterozygotes (P = 0.045). Compound heterozygosity was not invariably associated with severe disease with six (50%) having clinically mild disease at a median age of 57.5 yr and median disease duration of 16 yr. Inheriting two different SE-bearing alleles results in an increased risk of RA and, on average, greater disease severity. This is not, however, invariably associated with severe disease, making it of limited use as a predictor of prognosis.
authors.affiliation: Bloomsbury Rheumatology Unit, Middlesex Hospital, London.
authors.forename: J E
authors.initials: JE
authors.lastname: McDonagh
authors.forename: A
authors.initials: A
authors.lastname: Dunn
authors.forename: W E
authors.initials: WE
authors.lastname: Ollier
authors.forename: D J
authors.initials: DJ
authors.lastname: Walker
mesh_terms: D000328:Adult; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D000939:Epitopes / Q000235:genetics; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains