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

Objective. To examine the relationship between allelic polymorphisms of IgG receptors (Fc gammaR) and the development of lupus nephritis in a prospect ive study, and to determine the distribution of Fc gammaR haplotypes (Fc ga mma RIIA and Fc gamma RIIIA genotypes) in lupus patients and disease-free c ontrol 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. Fc gamma RIIA and Fc gamma RIIIA genotypes were determined using allele-specific polymerase chai n reaction. Results. Nephritis was present in 28% of patients at entry into the study a nd in 69% at the end of 3 years. In the nephritis group (n = 46), as well a s the entire SLE cohort, there was a predominance of genotypes with low-bin ding alleles (Fc gamma RIIa-R131 and Fc gamma RIIIa-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 homozy gous for either Fc<gamma>RIIa-H131 or Fc gamma RIIIa-V176). The frequency o f individuals homozygous for high-binding alleles at either locus decreased as the burden of disease increased (P < 0.002, by Mann-Whitney test). Ther e was no linkage disequilibrium between Fc<gamma>RIIA and Fc gamma RIIIA in Hispanics, yet in the SLE patients, there was a clear overrepresentation o f the Fc gamma RIIa-R131;Fc gamma RIIIa-F176 haplotype (SLE patients 48% ve rsus controls 30%) and a decrease in the frequency of the high-binding hapl otype (4% versus 23%) (P < 0.002). Conclusion. We observed an increase in the frequency of low-binding Fc<gamm a>R alleles in an SLE population with a high prevalence of renal disease. T he apparent selection for the Fc gamma RIIa-R131;Fc gamma RH1a-F176 haploty pe in Hispanic patients suggests that low-binding alleles of both Fc gamma RIIa and Fc gamma RIIIa confer risk for SLE and may act additively in the p athogenesis of disease, whereas the high-binding haplotype Fc gamma RIIa-H1 31;Fc gamma RIIIa-V176 is protective, particularly in the homozygous state.