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 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.


CONCLUSIONS
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.
Yangzhou University, Yangzhou, China; University of Alabama at, Birmingham.
Chaoling
C
Dong
Travis S
TS
Ptacek
David T
DT
Redden
Kui
K
Zhang
Elizabeth E
EE
Brown
Jeffrey C
JC
Edberg
Gerald
G
McGwin
Graciela S
GS
Alarcón
Rosalind
R
Ramsey-Goldman
John D
JD
Reveille
Luis M
LM
Vilá
Michelle
M
Petri
Aijian
A
Qin
Jianming
J
Wu
Robert P
RP
Kimberly
D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008181:Lupus Nephritis / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D017452:Receptors, IgG / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics
C496124:FCGR3A protein, human; D007074:Immunoglobulin G; D017452:Receptors, IgG