Higher Complement C4 Gene Copy Number Constitutes a Shared Genetic Risk Factor for Giant Cell Arteritis and IgA Vasculitis.

Low copy number (CN) of complement C4 isoforms and high CN of retroviral HERV-K elements are known risk factors for many immune-mediated inflammatory diseases (IMIDs), often showing sex-biased effects. Here, we assessed whether CN variation within the C4 gene contributes to giant cell arteritis (GCA) and IgA vasculitis (IgAV), two complex vasculitides involving complement dysregulation. C4A, C4B, and HERV-K CNs were imputed from genotypic data of 3,498 patients with GCA, 284 patients with IgAV, and 16,867 controls. We evaluated their associations with vasculitis risk overall and stratified by sex (inferred from genetic data), alongside classical HLA alleles. Contrary to other IMIDs, we identified higher C4 CN to confer risk to GCA and IgAV. Specifically, in GCA, higher C4B CN conferred risk in male patients (odds ratio (OR) 1.23, 95% confidence interval (CI) 1.07-1.42, P = 4.52 × 10-3, P adjusted by false discovery rate (PFDR) = 1.40 × 10-2). In IgAV, elevated C4A CN was significantly associated with disease susceptibility in the overall cohort (OR 1.68, 95% CI 1.22-2.30, P = 1.49 × 10-3, PFDR = 4.48 × 10-3), whereas C4B CN showed a male-biased trend, as observed in GCA (OR 1.46, 95% CI 1.02-2.08, P = 3.88 × 10-2, PFDR = 5.80 × 10-2). Conditional analyses confirmed that these associations were independent of classical HLA alleles. This study reveals sex-dependent variation in C4 CN as a novel genetic risk factor for GCA and IgAV, suggesting shared biologic mechanisms involving complement dysregulation, sustained inflammation, and vascular damage.