Complement gene variation drives sex biases in autoimmune disease.
Genome-wide association studies (GWASs) have previously identified extensive links between variability at the MHC locus and risk for autoimmunity. The MHC locus-associated risk is typically attributed to variations in class I and II HLA genes, which can directly alter the binding and presentation of autoantigens. Indeed, such mechanisms have been identified in several autoimmune diseases, including type I diabetes and rheumatoid arthritis.
However, non-HLA genes within the MHC locus are also highly variable and can show strong linkage disequilibrium with disease-associated HLA variants. Notably, the complement-encoding C4A and C4B genes within the MHC locus demonstrate high allelic and copy-number variability. Prior GWASs have directly implicated variation in C4A/B to risk of schizophrenia.
In a recent study, Kamitaki et al. provides compelling evidence that copy-number variation in C4A/B drives disease risk in systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS), which disproportionately affect women. Using large GWAS cohorts, the authors found that increased C4A/B copy number conferred strong protection from SLE and SS. Interestingly, these C4A/B variants were the same as those that conferred increased risk in prior GWASs of schizophrenia, which shows greater incidence and severity in men.
Consistent with these sex biases, the authors found that the strength of associations between C4A/B copy number and disease risk were strongest in men. The authors evaluated complement protein levels in cerebrospinal fluid and plasma from large, genetically-characterized cohorts of healthy donors and found that C4 protein levels were positively correlated with underlying C4A/B copy number and were consistently higher in men than women Interestingly, sex differences in C4 levels were most pronounced between the ages of 20 and 50, coinciding with peaks in the sex-biased disease incidence for schizophrenia in men and for SLE and SS in women.
These findings thus suggest a model whereby increased complement activity in men leads to more rapid clearance of antigens at sites of cell injury, which limits the emergence of adaptive (auto)immune responses but exerts potentially deleterious effects in the brain. Although the authors do not directly test this hypothesis (or the mechanism of increased copy-number adjusted C4 levels in men), their human genetics data provide a foundation for future experimental work and insight into the complexity of therapeutically targeting these pathways.
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