Role of Fcg Receptors IIA, IIIA, and IIIB in Susceptibility to Rheumatoid Arthritis

TIMOTHY R.D.J. RADSTAKE, ELISABETH PETIT, CIELINE PIERLOT, LEO B.A. van de PUTTE, FRANÇOIS CORNELIS, and PILAR BARRERA

ABSTRACT.

Objective. To investigate the role of Fcg receptor (FcgR) genes in susceptibility to rheumatoid arthritis (RA) using family based studies, to examine possible interactions between FcgR genotypes and the shared epitope (SE), and to assess linkage disequilibrium between FcgR loci.

Methods. Association studies were performed in 95 Caucasian, single-case, nuclear Caucasian families with both parents alive using haplotype based haplotype relative risk (HHRR) and transmission disequilibrium test (TDT) statistics. Three FcgR polymorphisms (FcgRIIA-131H/R, FcgRIIIA-158V/F, and FcgRIIIB-NA1/NA2) were genotyped using polymerase chain reaction methods. Linkage analysis was performed using 3 microsatellite markers (D1S498, D1S2844, D1S2762) flanking the FcgR region in an independent set of 90 Caucasian, multiple-case families.

Potential effects of disease heterogeneity, including sex and the presence of rheumatoid factor, SE, and erosive or nodular disease, were taken into account in the analysis. Logistic regression analysis was performed to determine whether FcgR alleles are independent risk factors for the susceptibility to and/or severity of RA. Linkage disequilibrium was calculated using pairwise linkage disequilibrium statistics.

Results. HHRR and TDT analysis showed no evidence of preferential transmission of any FcgR alleles studied, and there were no important associations with any given disease phenotype. Moreover, neither linkage to microsatellite markers close to the FcgR genes on chromosome 1 nor linkage disequilibrium between FcgR loci was present in our population. The distribution of inherited genotypes provided evidence for an interaction between the SE and the FcgRIIIA-158V allele and between the SE and the FcgRIIIA-158V–FcgRIIA-131H 2-locus haplotype since the combined presence of these factors increased the susceptibility to RA (OR 4.13, 95% CI 1.6–10.62 and OR 2.83, 95% CI 1.25–6.38, respectively). However, regression analysis showed that neither the 158V allele nor the 158V-131H haplotype contributed as independent factors to susceptibility or severity of RA.

Conclusion. Isolated FcgR genes do not play a major independent role in susceptibility to RA. To a limited extent, the presence of high-binding alleles at the FcgRIIIA locus or at the FcgRIIIA–FcgRIIA haplotype might predispose to RA in SE positive individuals. (J Rheumatol 2003;30:926-33)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
Fc GAMMA RECEPTOR
POLYMORPHISMS
ASSOCIATION ANALYSIS
LINKAGE ANALYSIS

From the Department of Rheumatology, University Medical Centre St. Radboud, Nijmegen, The Netherlands; and Laboratoire de Recherche Europeen sur la Polyarthrite Rhumatoïde, Universite Paris VII, Genopole, Evry, France.

T.R.D.J. Radstake, MD; L.B.A. van de Putte, MD, PhD; P. Barrera, MD, PhD, Department of Rheumatology, University Medical Centre St. Radboud; E. Petit, PhD; C. Pierlot, MSc; F. Cornelis, MD, PhD, Laboratoire de Recherche Europeen sur la Polyarthrite Rhumatoïde, Universite Paris VII.

Address reprint requests to Dr. T. Radstake, Department of Rheumatology, University Medical Centre St. Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: t.radstake@reuma.azn.nl

Submitted October 11, 2001; revision accepted October 21, 2002.

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