Je. Mcdonagh et al., COMPOUND HETEROZYGOSITY FOR THE SHARED EPITOPE AND THE RISK AND SEVERITY OF RHEUMATOID-ARTHRITIS IN EXTENDED PEDIGREES, British journal of rheumatology, 36(3), 1997, pp. 322-327
The objective was to explore the role of HLA-DRB1 genes in determining
disease severity in rheumatoid arthritis (RA). The population compris
ed 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-DRB104 variants was perfo
rmed using the Multiplex ARMS-RFLP technique. Compound heterozygote in
dividuals 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 suggest
ed. Individuals carrying no SE alleles expressed milder disease, as me
asured by the Spread Severity (SS) index, compared to compound heteroz
ygotes (P = 0.045). Compound heterozygosity was not invariably associa
ted 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. Inher
iting two different SE-bearing alleles results in an increased risk of
RA and, on average, greater disease severity. This is not, however, i
nvariably associated with severe disease, making it of limited use as
a predictor of prognosis.