Fcγ Receptor IIIa Single-Nucleotide Polymorphisms and Haplotypes Affect Human IgG Binding and Are Associated With Lupus Nephritis in African Americans

Objective. To investigate whether the Fc gamma receptor IIIa-66L/R/H (Fc gamma RIIIa-66L/R/H) polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by Fc gamma RIIIa66L/R/H and Fc gamma RIIIa-176F/V, as well as copy number variation (CNV), confer risk of developing systemic lupus erythematosus (SLE) and lupus nephritis. Methods. Fc gamma RIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG-binding assays. Using Pyrosequencing methodology, FCGR3A single-nucleotide polymorphism and CNV genotypes were determined in a cohort of 1,728 SLE patients and 2,404 healthy controls. Results. The Fc gamma RIIIa-66L/R/H (rs10127939) polymorphism influenced ligand binding capacity in the presence of the Fc gamma RIIIa-176V (rs396991) allele. There was a trend toward an association of the low-binding Fc gamma RIIIa-176F allele with lupus nephritis among African Americans (P = 0.0609) but not among European Americans (P > 0.10). Nephritis among African American patients with SLE was associated with Fc gamma RIIIa low-binding haplotypes containing the 66L/R/H and 176F variants (P = 0.03) and with low-binding genotype combinations (P = 0.002). No association was observed among European American patients with SLE. The distribution of FCGR3A CNV was not significantly different among controls and SLE patients with or without nephritis. Conclusion. Fc gamma RIIIa-66L/R/H influences ligand binding. The low-binding haplotypes formed by 66L/R/H and 176F confer enhanced risk of lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or lupus nephritis in either African Americans or European Americans.