Fc-gamma receptor polymorphisms differentially influence susceptibility to systemic lupus erythematosus and lupus nephritis

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OBJECTIVE: To determine relevant Fc-gamma receptor (FcgammaR) polymorphisms in relation to susceptibility to SLE and LN, and to determine the functional consequences of genetic associations found. METHODS: Using multiplex ligation-dependent probe amplification, copy number regions (CNRs) and relevant known functional single nucleotide polymorphisms of FcgammaRII and FcgammaRIII were determined in a LN-enriched cohort of 266 Dutch Caucasian SLE patients and 919 healthy Caucasian controls. Expression of FcgammaRs on leukocytes was assessed using flow cytometry. RESULTS: In multivariable analysis, low copy number of CNR1 (includingFCGR3B; odds ratio (OR) 2.04; 95% CI: 1.29, 3.23),FCGR2A-131RR (OR 2.00; 95% CI: 1.33, 2.99), and the 2B.4 haplotype ofFCGR2B(OR 1.59; 95% CI: 1.13, 2.24), but notFCGR2Copen reading frame, were significantly (all P < 0.01) and independently associated with susceptibility to SLE. The 2B.4 haplotype was negatively associated with LN and led to surface expression of FcgammaRIIb on neutrophils and monocytes. CONCLUSION: This study is the first to investigate the most relevant and functional single nucleotide polymorphisms and copy number variations of FcgammaRII and FcgammaRIII polymorphisms in one study population, enabling the determination of the individual contribution of each polymorphism in multivariable analysis. Three polymorphisms were shown to be independently associated with susceptibility to SLE. The novel findings of a negative association of the 2B.4 haplotype with LN, and increased expression of FcgammaRIIb on neutrophils and monocytes as a result of this 2B.4 haplotype warrant future research in the role of these cells and FcgammaRs in the pathogenesis of SLE and LN.