Association between tumor necrosis factor receptor II and familial, but not sporadic, rheumatoid arthritis: evidence for genetic heterogeneity.
OBJECTIVE
Tumor necrosis factor alpha (TNFalpha) 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.


CONCLUSIONS
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.
Dieudé
Philippe
P
GenHotel, Evry-Genopole, France. dieude@polyarthrite.net
Petit
Elisabeth
E
Cailleau-Moindrault
Séverine
S
Osorio
José
J
Pierlot
Céline
C
Martinez
Maria
M
Fauré
Sabine
S
Alibert
Olivier
O
Lasbleiz
Sandra
S
De Toma
Claudia
C
Bardin
Thomas
T
Prum
Bernard
B
Cornélis
François
F
D000328:Adult; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000032:analysis; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D004247:DNA