The Fc gamma receptor IIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians

Objective. To determine whether inheritance of Fey receptor (Fc gammaR) all eles conferring lower affinity for IgG binding increases the risk of develo ping lupus nephritis. Methods. We compared the frequency of low-affinity alleles of two Fc gammaR polymorphisms (Fc gamma RIIA and Fc gamma RIIIA) among 235 patients with s ystemic lupus erythematosus (SLE) and proven nephritis (nephritis patients) and among 352 SLE patients with no evidence of renal disease (non-nephriti s control subjects). The ethnic distribution of patients in the study was 4 9% Caucasian, 20% Hispanic, 17% Asian/Pacific Islander, 12% African America n, and 2% from other ethnic groups. All patients were genotyped for the Fc gamma RIIA-131R/H and Fc gamma RIIIA-158V/F polymorphisms. We used continge ncy table analysis to compare allele and genotype distributions for nephrit is patients and non-nephritis control subjects, including ethnic-specific s trata. Multivariate logistic regression analyses included sex and disease d uration as covariates. Results. Univariate and multivariate analyses demonstrated a striking assoc iation between the low-affinity Fc gamma RIIIA-158F allele and FF genotype and the risk of nephritis among Caucasians, but not among non-Caucasians (m ultivariate odds ratio [OR] 2.6 for Caucasians with FF genotype), (P = 0.00 17). This association was even stronger among Caucasians with severe nephri tis (OR 4.4, P < 0.0001). In contrast, inheritance of the low-affinity Fc<g amma>RIIA-13IR allele (and RR genotype) was not associated with an increase d risk of lupus nephritis among any of the ethnic groups examined. Conclusion. The Fc gamma RIIIA-158F allele is a major risk factor for the d evelopment of lupus nephritis among Caucasians, but not among non-Caucasian s. These results suggest that ethnic variation is critical in defining the specific genetic factors underlying the pathogenesis of SLE, and they have important prognostic and therapeutic implications as well.