Fcγ receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans.

Pubmed ID: 24782186

Pubmed Central ID: PMC4069204

Journal: Arthritis & rheumatology (Hoboken, N.J.)

Publication Date: May 1, 2014

MeSH Terms: Humans, Case-Control Studies, Risk Factors, Alleles, Genetic Predisposition to Disease, Haplotypes, Polymorphism, Single Nucleotide, Genotype, Phenotype, Immunoglobulin G, Protein Binding, Lupus Nephritis, Receptors, IgG, White People, Black or African American

Grants: K24-AR-002138, P01-AR-049084, P30 AR048311, P30-AR-048311, P60-2AR-30692, P60-AR-048095, R01-A-R043727, R21 HL117652, UL1 TR000371, UL1 TR001079, UL1-RR-025741, UL1-TR-00165, UL1 RR025741, P60 AR048095, UL1 TR000165, R01 AR043727, K24 AR002138, P60 AR030692, P01 AR049084

Authors: McGwin G, Dong C, Wu J, Ptacek TS, Redden DT, Zhang K, Brown EE, Edberg JC, Alarcón GS, Ramsey-Goldman R, Reveille JD, Vilá LM, Petri M, Qin A, Kimberly RP

Cite As: Dong C, Ptacek TS, Redden DT, Zhang K, Brown EE, Edberg JC, McGwin G Jr, Alarcón GS, Ramsey-Goldman R, Reveille JD, Vilá LM, Petri M, Qin A, Wu J, Kimberly RP. Fcγ receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans. Arthritis Rheumatol 2014 May;66(5):1291-9.

Studies:

A Case Controlled Etiologic Study of Sarcoidosis (ACCESS)

Abstract

OBJECTIVE: To investigate whether the Fcγ receptor IIIa-66L/R/H (FcγRIIIa-66L/R/H) polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcγRIIIa-66L/R/H and FcγRIIIa-176F/V, as well as copy number variation (CNV), confer risk of developing systemic lupus erythematosus (SLE) and lupus nephritis. METHODS: FcγRIIIa 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 FcγRIIIa-66L/R/H (rs10127939) polymorphism influenced ligand binding capacity in the presence of the FcγRIIIa-176V (rs396991) allele. There was a trend toward an association of the low-binding FcγRIIIa-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 FcγRIIIa 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: FcγRIIIa-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.