Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus

Objectives. Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. Methods. This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaR11A and FcgammaRI11A) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. Results. We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaR111A were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. Conclusions. The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.