Objectives: Fcγ-receptors (FcγRs) are potent immune-modulators. FcγRs-genes encompass a complex region, polymorphic by both single nucleotide polymorphisms (SNPs) and copy number variation (CNV). The heterogeneity of rheumatoid arthritis (RA) combined with the genetic-complexity of FcγRs-genes may be the cause of inconsistent findings in previous RA-studies on FcγR-SNPs. Since there is increasing evidence that anti-citrullinated peptide antibodies (ACPA)-positive RA and ACPA-negative RA have different genetic background, we investigated whether FcγRIIIA158V/F-SNP differently associates with ACPA-positive and ACPA-negative RA. Moreover, this study is the first to assess whether FcγRIIIA-gene CNV affects the association of the FcγRIIIA158V/F-SNP with RA and if FcγRIIIA-gene CNV confers risk to RA.
Methods: This study comprises 945 RA patients and 388 healthy controls, all Dutch-Caucasians. FcγRIIIA158V/F-SNP was genotyped using Sequenom. CNV of FcγRIIIA-gene was determined in 456 RA patients and 285 controls using Multiplex Ligation-dependent Probe Amplification (MLPA). Associations between genotypes and RA were analysed stratifying for the presence/absence of ACPA and CNV.
Results: In all RA patients the FcγRIIIA158V/F-SNP was not associated with RA. In ACPA+RA (N=358), the VV-genotype was more prevalent in cases than controls (18.4% versus 13.2%, OR=1.5, P=0.05). After stratification for CNV the VV-genotype was associated with RA in general (N=426) (OR=1.6, 95%CI 0.97-2.6, P=0.05) and with ACPA+RA (N=135) (OR=2.1, 95%CI 1.2-3.8, P=0.009) but not with ACPA-RA. The distribution of CNV was not significantly different between RA-patients and controls.
Conclusion: The FcγRIIIA-158 VV-genotype confers risk to ACPA+RA; this association increased slightly after correction for CNV of the FcγRIIIA-gene. CNV itself was not associated with RA-susceptibility.