8.1
TITLE: ANALYSES ON THE ASSOCIATION OF Fc&ggr;RECEPTOR FAMILY AND TNFR2 (TNFRSF1B) POLYMORPHISMS WITH SUSCEPTIBILITY TO RHEUMATOID ARTHRITIS IN JAPANESE

Chieko Kyogoku,1 Naoyuki Tsuchiya,1 Kunio Matsuta,2 Tsukasa Shibue,1 Katsushi Tokunaga.1

1Dept of Human Genetics, The University of Tokyo, Tokyo, Japan; 2Matsuta Clinic, Tokyo, Japan

We recently reported a new polymorphism of Fc&ggr;RIIB gene (FCGR2B), which alters Ile at position 232 to Thr (I232T), within the transmembrane domain, and its association with SLE in Japanese. Functional importance of Fc&ggr;RIIB, as well as other Fc&ggr;Rs, in RA has previously been shown; therefore, we examined whether FCGR polymorphisms were associated with susceptibility to RA in Japanese. TNFR2 is another candidate gene located on one of the chromosomal regions implicated from genome–wide linkage studies, and recent studies demonstrated that TNFR2–196R/R genotype was significantly increased in familial RA in Caucasians. Our previous study showed a tendency of increase in the frequency of 196R/R genotype in Japanese sporadic RA (P = 0.10). Therefore, we genotyped additional patients and controls to further test the association of 196R/R in Japanese.

Genotyping of FCGR2B–I232T, FCGR2A–H131R, FCGR3A–F176V, FCGR3B–NA1/2 and TNFR2–M196R polymorphisms were performed in 382 Japanese patients and 303 healthy individuals for FCGRs, and in 588 patients and 308 controls for TNFR2. Significant difference in the distribution of genotype, allele carrier and allele frequencies was not observed between patients with RA and healthy individuals in FCGR genes. However, when the subjects were stratified according to the carriage of HLA–DRB1 shared epitope (SE), significant increase of FCGR3A–176F/F genotype was observed in SE positive RA (55.9%) compared with SE positive controls (41.5%) (P = 0.009).

As for TNFR2, a tendency of increase of 196R/R genotype in RA (2.9%) compared with healthy individuals (1.0%) was observed (P = 0.07). However, estimation of genotype relative risk, which adjusts control data for Hardy–Weinberg equilibrium and has a higher power of detecting association, indicated that TNFR2–196R/R genotype was significantly increased in RA compared with controls (&khgr;2 = 6.2, P = 0.01, OR:2.3).

These results indicated that FCGR3A–176F/F genotype confers risk for RA through genetic interaction with HLA–DRB1 SE, and TNFR2–196R/R genotype may be a weak, but true, risk factor in the sporadic RA, in Japanese.