Open AccessAssociation between tumor necrosis factor receptor II and familial, but not sporadic, rheumatoid arthritis: Evidence for genetic heterogeneity
Author(s) -
Dieudé Philippe,
Petit Elisabeth,
CailleauMoindrault Séverine,
Osorio José,
Pierlot Céline,
Martinez Maria,
Fauré Sabine,
Alibert Olivier,
Lasbleiz Sandra,
De Toma Claudia,
Bardin Thomas,
Prum Bernard,
Cornélis François
Publication year - 2002
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.10101
Subject(s) - linkage disequilibrium , transmission disequilibrium test , haplotype , genetic association , genotype , genetics , medicine , rheumatoid arthritis , population , context (archaeology) , locus (genetics) , odds ratio , immunology , biology , single nucleotide polymorphism , gene , paleontology , environmental health
Objective Tumor necrosis factor α (TNFα) binds the receptors TNFRI and TNFRII. Results of genome scans have suggested that TNFR2 is a candidate rheumatoid arthritis (RA) locus. A case–control study in a UK Caucasian population has shown an association between a TNFR2 genotype (196R/R in exon 6) and familial, but not sporadic, RA. The present study was undertaken to test this association in the French Caucasian population. Methods To test for an association in sporadic RA, 100 families were genotyped for the 196M/R polymorphism and analyzed using the transmission disequilibrium test and haplotype relative risk. To test for an association in familial RA, RA index cases from 100 affected sibpair (ASP) families were genotyped for 196M/R. Linkage analysis was performed with 3 TNFR2 microsatellite markers. Results The TNFR2 196R/R genotype was not associated with sporadic RA (odds ratio [OR] 0.59, P = 0.72), but was associated with familial RA (OR 4.0, P = 0.026). The association was most marked in the context of TNFR2 “twin‐like” RA sibs (affected sibs sharing both TNFR2 haplotypes) (OR 9.2, P = 0.0017). Linkage analysis results were consistent with the association; most of the TNFR2 linkage evidence was found in the subgroup of families with 196R/R ASP index cases. Conclusion This study is the first to replicate evidence of the involvement of TNFR2 in RA genetic heterogeneity. Our data refine the initial hypothesis, to suggest that a TNFR2 recessive factor, in linkage disequilibrium with the 196R allele, plays a major role in a subset of families with multiple cases of RA.