Evidence for functional variation of the death receptor 3 gene predisposing rheumatoid arthritis

Apoptosis of the cell is important for the pathogenesis of autoimmune diseases. We identified the death receptor 3 (DR3) gene, a family of apoptosis-inducing Fas gene6, containing four single nucleotide polymorphisms and one locus of a 14-nucleotide deletion within exon 5 and intron 5. This haplotype resulted in insertion of a portion of intron 5 into the coding sequence or deletion of exon 6, and generated premature stop codons. The thus generated mutant DR3 lacking death domain assembled with a wild-type DR3 molecule to inhibit apoptosis, and apoptosis induction by anti-DR3 antibody was impaired in the lymphocytes of individuals with mutation. We also found that experimental collagen-induced arthritis was ameliorated by anti-DR3 antibody treatment, and the haplotype was clinically found in increased frequency in familial patients with RA and the patients who underwent joint surgery as compared with controls (P < 0.0006). We surmise that this mutation is responsible for impairment of apoptosis induction in patients with rheumatoid arthritis, which may predispose to arthritic joint destruction and autoimmunity.