POLYMORPHISM IN THE LMP2 GENE INFLUENCES DISEASE SUSCEPTIBILITY AND SEVERITY IN HLA-B27 ASSOCIATED JUVENILE RHEUMATOID-ARTHRITIS

Objective. To determine the potential contribution of the MHC class II region proteasome subunit gene, LMP2, to disease susceptibility, seve rity, and phenotype in patients with juvenile rheumatoid arthritis (JR A). Methods. A CfoI restriction site polymorphism in the coding region of the LMP2 gene was evaluated in 279 patients with JRA and 107 healt hy controls of similar ethnicity. Patients were divided into 5 groups on the basis of clinical presentation; 46% had early onset pauciarticu lar disease, 10% early onset polyarticular, 10% late onset pauciarticu lar, 20% late onset polyarticular, and 11% systemic onset arthritis. T he influence of this LMP2 polymorphism on susceptibility to disease, c linical subtype of disease at onset (age and number of joints involved ), progression and severity of joint disease (pauci to polyarticular c ourse and radiographic changes), and occurrence of inflammatory eye di sease was evaluated. Results. Comparison of genotypes revealed a signi ficantly increased prevalence of homozygosity for the LMP2 B allele (L MP2 BE genotype) in patients who were older (greater than or equal to 6 years) at onset of disease (65%, p < 0.05), particularly in those wi th pauciarticular (71%) involvement at presentation (p < 0.05), compar ed to controls (51%). The BE genotype was also more prevalent in patie nts with a polyarticular course, either from onset (63%) or those who progressed from pauciarticular disease (69%), compared with controls ( p = 0.05 and < 0.05, respectively). Stratification for HLA-B27 and DR4 , the HLA alleles most frequently associated with late onset pauciarti cular and late onset polyarticular JRA, respectively, revealed a persi stent effect of LMP2 BE homozygosity on disease susceptibility and phe notype that remained statistically significant in HLA-B27 positive chi ldren, and was not due to linkage disequilibrium. Conclusion, We show that homozygosity for the B allele of the proteasome subunit LMP2 incr eases susceptibility to certain subgroups of JRA, and influences the p henotype of disease, predisposing to a more progressive and severe art icular disease.