A TNFR1 genotype with a protective role in familial rheumatoid arthritis

Results of genome scans in rheumatoid arthritis (RA) have suggested that the tumor necrosis factor receptor I (TNFRI) and TNFRII loci (TNFR1 and TNFR2) are susceptibility loci. A TNFR2 polymorphism was found to be associated with familial RA. TNFR1 is mutated in TNFR-associated periodic syndrome (TRAPS). We undertook this study to test the TNFR1 exonic polymorphism closest to the TRAPS mutations site (+36 A/G) for association with RA.

DNA samples were available from two groups of the French Caucasian population: 1) 100 families with 1 RA patient and both parents and 2) 86 RA index patients from families with at least 2 siblings with RA (affected sibpairs [ASPs]). The +36 A/G polymorphism of TNFR1 was genotyped by polymerase chain reaction-restriction fragment length polymorphism. The analysis was performed using the transmission disequilibrium test, the genotype relative risk, and a linkage-based test previously described.

A negative association between RA and the +36 A/A genotype, suggested in the first sample (P = 0.084), was demonstrated in the second (ASP RA) sample (odds ratio [OR] 0.465; P = 0.012) and confirmed by the linkage-based test (OR 0.17; P = 0.008). The protective genotype, present in 41% of controls, was less frequent in RA patients: 33% in the first sample, 24% in the ASP RA sample, and 11% in the linkage-derived subgroup. Distribution of both TNFR2 196 R/R and TNFR1 +36 A/A genotypes in the ASP RA sample showed that both suspected genotypes were exclusive.

We found evidence for an association between RA and a TNFR1 protective genotype, restricted to familial RA. Distribution of the TNFR2 196 R/R and TNFR1 +36 A/A genotypes in familial RA could suggest an interaction between TNFR1 and TNFR2 in the genetic susceptibility for RA.