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.

DNA pooling is a potential tool for the efficient analysis of the large numbers of samples and DNA markers that are necessary for genome-wide association studies. A simple accurate method for measuring total allele differences in comparisons between two pools containing large numbers of DNA samples is presented. This method compares relative peak height differences between electrophoretograms for each allele of a microsatellite. The method was evaluated by the analysis of 11 microsatellite markers and DNA pooled sample sizes of 50, 100, and 200 individual DNA samples from the same number of different subjects. Pools were created from previously individually genotyped subjects and constructed so that the pool comparisons would provide real total allele differences varying from 0% to 55%. Calculated pool differences were then compared with the real total allele differences determined by individual genotyping results. Together over 200 comparisons demonstrated a correlation coefficient of 0.96, which compared favorably with other previous methods of analysis. This method could provide a rapid screen for total allele differences of greater than 10%, a threshold that should be applicable to detecting low relative risk genes in common diseases. Therefore, these studies suggest that DNA pooling could be a useful tool in association studies for the determination of candidate regions for a range of complex genetic diseases.

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.