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

Abstract

Objective To determine whether inheritance of Fcγ receptor (FcγR) alleles conferring lower affinity for IgG binding increases the risk of developing lupus nephritis. Methods We compared the frequency of low‐affinity alleles of two FcγR polymorphisms (FcγRIIA and FcγRIIIA) among 235 patients with systemic lupus erythematosus (SLE) and proven nephritis (nephritis patients) and among 352 SLE patients with no evidence of renal disease (non‐nephritis control subjects). The ethnic distribution of patients in the study was 49% Caucasian, 20% Hispanic, 17% Asian/Pacific Islander, 12% African American, and 2% from other ethnic groups. All patients were genotyped for the FcγRIIA‐131R/H and FcγRIIIA‐158V/F polymorphisms. We used contingency table analysis to compare allele and genotype distributions for nephritis patients and non‐nephritis control subjects, including ethnic‐specific strata. Multivariate logistic regression analyses included sex and disease duration as covariates. Results Univariate and multivariate analyses demonstrated a striking association between the low‐affinity FcγRIIIA‐158F allele and FF genotype and the risk of nephritis among Caucasians, but not among non‐Caucasians (multivariate odds ratio [OR] 2.6 for Caucasians with FF genotype), (P = 0.0017). This association was even stronger among Caucasians with severe nephritis (OR 4.4, P < 0.0001). In contrast, inheritance of the low‐affinity FcγRIIA‐131R allele (and RR genotype) was not associated with an increased risk of lupus nephritis among any of the ethnic groups examined. Conclusion The FcγRIIIA‐158F allele is a major risk factor for the development of lupus nephritis among Caucasians, but not among non‐Caucasians. 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.

Fcγ Receptor IIIa Single‐Nucleotide Polymorphisms and Haplotypes Affect Human IgG Binding and Are Associated With Lupus Nephritis in African Americans

“…Surprisingly, we found no trend of association in European Americans, despite our population size. One study did show such an association (), and the basis for that finding may lie in the allele frequencies found in the control group, which were different from those found in our study and other studies ().…”

Fcγ receptor gene polymorphisms in Japanese patients with systemic lupus erythematosus: Contribution of FCGR2B to genetic susceptibility

“…In addition to the FCGR2B ‐232I/T polymorphism, the FCGR3A ‐176V/F polymorphism was also significantly associated with susceptibility to SLE in Japanese patients in this study, thus replicating previous observations in different populations by several groups (36–40). The Lathrop‐type analysis suggested that the association of FCGR3A ‐176F is perhaps weaker than that of FCGR2B , apart from a genotypic difference that stems from slight deviations from Hardy‐Weinberg equilibrium in the control population.…”

Role of the Fcγ receptor IIa polymorphism in susceptibility to systemic lupus erythematosus and lupus nephritis: A meta‐analysis

“…Characteristics of eligible studies. Twenty‐eight comparisons from 20 studies addressing the relationship between FcγRIIa‐R/H131 and susceptibility to SLE and/or the development of lupus nephritis were identified (4–19, 30–33). Three reports (5, 16, 30) were excluded because of extensive overlapping with other included publications.…”