Tumor necrosis factor alpha 5 '-flanking region, tumor necrosis factor receptor II, and HLA-DRB1 polymorphisms in Japanese patients with rheumatoid arthritis

Objective. New polymorphisms affecting transcriptional activity were recent ly reported within the 5'-flanking region of the tumor necrosis factor ex g ene (TNFA). In addition, genome-wide linkage screening indicated 1p36 as on e of the candidate chromosomal regions where the TNF receptor II gene (TNFR 2) is located. In the present study, HLA-DRB1, TNFA promoter, and TNFR2 gen otypes were determined to examine whether these polymorphisms are associate d with rheumatoid arthritis (RA), either independently or in combination. Methods. Genotypes of HLA-DRB1, TNFA upstream promoter, and TNFR2 codon 196 were determined in 545 Japanese patients with RA and 265 healthy controls. Association of these genes with susceptibility to RA was analyzed both ind ependently and after stratification by one of the genotypes. Results. As expected, the HLA-DRB1 shared epitope was strongly associated w ith RA, In addition, a significant negative association of DRB1*1405 and 13 02 was observed, Furthermore, DRB1*1405 was suggested to possess a protecti ve role for the development of RA in DRB1*0405-positive individuals. A sign ificant increase in TNFA-U02 in RA was detected, which was not independent of DRB1*0405, A significant association was not observed between TNFR2-196M /R polymorphism and RA, Conclusion. Among the 3 genes examined in this; study, HLA-DRB1 was conside red to be most strongly associated with RA.