Low-binding alleles of fcγ receptor types IIA and IIIA are inherited independently and are associated with systemic lupus erythematosus in hispanic patients

Abstract

Objective. To examine the relationship between allelic polymorphisms of IgG receptors (FcγR) and the development of lupus nephritis in a prospective study, and to determine the distribution of FcγR haplotypes (FcγRIIA and FcγRIIIA genotypes) in lupus patients and disease-free control subjects. Methods. We studied 67 Hispanic systemic lupus erythematosus (SLE) patients from a prospective study of outcome and 53 disease-free control subjects. Patients were followed up longitudinally for 3 years. FcγRIIA and FcγRIIIA genotypes were determined using allele-specific polymerase chain reaction. Results. Nephritis was present in 28% of patients at 11entry into the study and in 69% at the end of 3 years. In the nephritis group (n = 46), as well as the entire SLE cohort, there was a predominance of genotypes with low-binding alleles (FcγRIIa-R131 and FcγRIIIa-F176) at both loci (SLE nephritis patients 89% versus controls 62%; P < 0.002; odds ratio 0.20 [95% confidence interval 0.05-0.6] for risk of nephritis in individuals homozygous for either FcγRIIa-H131 or FcγRIIIa-V176). The frequency of individuals homozygous for high-binding alleles at either locus decreased as the burden of disease increased (P < 0.002, by Mann-Whitney test). There was no linkage disequilibrium between FcγRIIA and FcγRIIIA in Hispanics, yet in the SLE patients, there was a clear overrepresentation of the FcγRIIa-R131;FcγRIIIa-F176 haplotype (SLE patients 48% versus controls 30%) and a decrease in the frequency of the high-binding haplotype (4% versus 23%) (P < 0.002). Conclusion. We observed an increase in the frequency of low-binding FcγR alleles in an SLE population with a high prevalence of renal disease. The apparent selection for the FcγRIIa-R131;FcγRIIIa-F176 haplotype in Hispanic patients suggests that low-binding alleles of both FcγRIIa and FcγRIIIa confer risk for SLE and may act additively in the pathogenesis of disease, whereas the high-binding haplotype FcγRIIa-H131;FcγRIIIa-V176 is protective, particularly in the homozygous state.