FC-GAMMA-RIIA ALLELES ARE HERITABLE RISK-FACTORS FOR LUPUS NEPHRITIS IN AFRICAN-AMERICANS

Allelic variants of Fc gamma R confer distinct phagocytic capacities p roviding a mechanism for heritable susceptibility to immune complex di sease, Human Fc gamma RIIa has two codominantly expressed alleles, R13 1 and H131, which differ substantially in their ability to ligate huma n IgG2. The Fc gamma RIIa-H131 is the only human Fc gamma R which reco gnizes IgG2 efficiently and optimal IgG2 handling occurs only in the h omozygous state. Therefore, since immune complex clearance is essentia l in SLE, we hypothesized that Fc gamma RIIA genes are important disea se susceptibility factors for SLE, particularly lupus nephritis, In a two-stage cross-sectional study, we compared the distribution of Fc ga mma RIIA alleles in African Americans with SLE to that in African Amer ican non-SLE controls. A pilot study of 43 SLE patients and 39 control s demonstrated a skewed distribution of Fc gamma RIIA alleles, with on ly 9% of SLE patients homozygous for Fc gamma RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P = 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 no n-SLE controls. The altered distribution of Fc gamma RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distr ibution showed a highly significant decrease in Fc gamma RIIA-H131 as the likelihood for lupus nephritis increased (P = 0.0004) consistent w ith a protective effect of the Fc gamma RIIA-H131 gene, The skewing in the distribution of Fc gamma RIIA alleles identifies this gene as a r isk factor with pathophysiologic importance for the SLE diathesis in A frican Americans.