GENETIC SUSCEPTIBILITY TO EARLY ONSET PAUCIARTICULAR JUVENILE CHRONIC ARTHRITIS - A STUDY OF HLA AND COMPLEMENT MARKERS IN 158 BRITISH PATIENTS

To investigate the genetics of susceptibility to early onset pauciarticular juvenile chronic arthritis (JCA), 158 unrelated ethnic British patients with a mean disease onset of 3.2 years, together with controls, were tested for HLA-A, B, C, and DR antigens. Additionally, 117 patients were also investigated for complement Bf and C4 markers. New observations included an increased frequency of the C4B 2 allotype (p corrected(pc) < 0.02) and C4A 4,B 2 phenotype (p < 0.0005). Findings suggested a unique increase of the haplotype HLA-DRw8, BF*S, C4A*4, C4B*2, HLA-B39, possibly predisposing to more severe disease. Strong positive associations were confirmed with HLA antigens A2 (pc = 2.5 .times. 10-8), DRw8 (pc = 3.5 .times. 10-14), DR5 (pc < 0.02), DRw52 (pc = 2.8 .times. 10-6) and DR5, w8 phenotype (pc = 3.9 .times. 10-6), and negative associations with DR7 (pc = 5.8 .times. 10-7), DR4 (pc < 0.002), and DRw53 (pc = 0.004). Antinuclear antibody (ANA) seropositivity correlated with DR5 (p < 0.02), and in children with chronic iridocyclitis (CIR) Bw62 incidence was raised (p < 0.03) and B44 reduced (p < 0.03). HLA-A2 was found in 88% of ANA+, CIR+ patients (p < 0.01). A significant excess of DR5, w8 heterozygotes was present (relative risk = 41.1) and a lack of corresponding homozygotes. Results are inconsistent with a recessive, dominant, or intermediate mode of inheritance of susceptibility, and favour the existence of at least two DR linked ''disease'' genes. Moreover, there may be an interaction in heterozygotes of combinatorial factors associated with DR5 and DRw8 in enhancing susceptibility. Possible immunogenetic mechanisms underlying the observed associations with three antigen classes are discussed. Evidence here suggests a role for the HLA-DQ locus in determining susceptibility to this disease.