Higher complement C4 gene copy number constitutes a shared genetic risk factor for giant cell arteritis and IgA vasculitis

Objective 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. Methods C4A , C4B and HERV‐K CNs were imputed from genotypic data of 3,498 GCA patients, 284 IgAV patients and 16,867 controls. We evaluated their associations with vasculitis risk overall and stratified by sex (inferred from genetic data), alongside classical human leukocyte antigen (HLA) alleles. Results 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 (OR = 1.23 (1.07 ‐ 1.42), p = 4.52 x 10 ‐3 , p FDR = 1.40 x 10 ‐2 ). In IgAV, elevated C4A CN was significantly associated with disease susceptibility in the overall cohort (OR = 1.68 (1.22 ‐ 2.30), p = 1.49 x 10 ‐3 , p FDR = 4.48 x 10 ‐3 ), while C4B CN showed a male‐biased trend, as observed in GCA (OR = 1.46 (1.02 ‐2.08), p = 3.88 x 10 ‐2 , p FDR = 5.80 x 10 ‐2 ). Conditional analyses confirmed that these associations were independent of classical HLA alleles. Conclusion This study reveals sex‐dependent variation in C4 CN as a novel genetic risk factor for GCA and IgAV, suggesting shared biological mechanisms involving complement dysregulation, sustained inflammation and vascular damage.