Identification of a genetic risk factor for systemic juvenile rheumatoid arthritis in the 5 '-flanking region of the TNF alpha gene and HLA genes

Objective. To study polymorphisms in the 5'-flanking promoter/enhancer regi on of the tumor necrosis factor alpha (TNF alpha) gene and in the coding re gions of HLA class I and class II genes, in order to. better understand the genetic background of juvenile rheumatoid arthritis (JRA). Methods. One hundred eleven Japanese JRA patients (50 with systemic disease , 29 with pauciarticular disease, and 32 with polyarticular disease) and 57 5 healthy Japanese subjects were examined for the allele frequencies of the TNF alpha, HLA-A, and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DP A1, and DPB1) genes, by DNA typing using the polymerase chain reaction-sequ ence-specific oligonucleotide probe method. Results. The frequencies of the polymorphic allele at positions -1,031 (T t o C substitution, termed -1,031C), -863 (C to A, termed -863A), and -857 (C to T, termed -857T) of the TNF alpha gene in patients with systemic JRA, b ut not in those with polyarticular or pauciarticular JRA, were significantl y higher than in the healthy controls, The allele frequencies of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, were signifi cantly higher than in controls. Linkage analysis showed that the presence o f both the TNF alpha -857T allele and DRB1*0405 yielded a significantly inc reased odds ratio (3.84), while the presence of only 1 of them did not yiel d a high odds ratio (0.87 and 1.58). Conclusion. The -1,031C/-863A allele and the -857T allele of the TNF alpha gene, both of which are related to high production of tumor necrosis factor alpha, are associated with systemic JRA, The -857T allele may enhance the effect of the DRB1*0405/DQB1*0401 haplotype in predisposing to development of systemic JRA.