Distinct effects of complement C4A and C4B copy number in Systemic Sclerosis serological and clinical subtypes

Objective Complement component 4 (C4), encoded by C4A and C4B within the major histocompatibility complex (MHC) on chromosome 6, regulates the immune response and clears immune complexes. Variable copy number (CN) of C4 genes and retroviral HERV‐K element influence its function. Given the relationship of C4 CN with SSc risk, we assessed associations with SSc clinical and serological subtypes. Methods We compared imputed C4 CNs across SSc subgroups (4,049 ACA + ; 2,200 ATA + ; 577 ARA + ; 1,078 triple negative patients (TN); 6,295 limited cutaneous (lcSSc); 2,946 diffuse cutaneous (dcSSc)) and 17,991 controls. We evaluated associations with SSc subtypes, identifying C4‐independent HLA alleles. Results Lower C4 CN and higher HERV‐K CN were associated with increased risk in all SSc subgroups. ATA + patients showed the strongest association, particularly with C4A (OR=1.88) and differences in C4A CN association were more pronounced between autoantibody subgroups (ATA + vs ACA + , p = 4x10 ‐11 ) than between clinical subgroups (dcSSc vs lcSSc, p = 1x10 ‐4 ). In ACA + patients, only low C4B CN showed a significant association to SSc risk (p=1.23x10 ‐5 ). We also observed sex‐biased associations: dcSSc, ATA + and ARA + males showed stronger effects for C4A and ACA + and lcSSc females for C4B . Finally, our results suggest that the HLA alleles associated with SSc subgroups are independent of C4 CN. Conclusion This study highlights distinct genetic contributions of C4A and C4B in SSc subtypes susceptibility. Our findings suggest that lower C4 CNs, particularly C4A , increase the risk of the severe dcSSc subtype, potentially through a mechanism involving immune complex clearance.