Our data support a polygenic model of organ-specific autoimmunity in SSc, with strong statistical evidence for IL-6- and NF-κB-associated genes (IL6ST, IRAK1, REL, and TNFAIP3) contributing to cutaneous and vascular pathologies, while variants in interferon and apoptotic regulation genes (SAMD9L, TREX1, and DNASE1L3) may underlie fibrotic and glandular involvement. The gene discussed is DNASE1L3; the disease is systemic sclerosis.