By integrating antibody profiling and the targeted sequencing of autoimmune-related genes, we identified a set of candidate variants—particularly in SAMD9L, IRAK1, REL, IL6ST, TNFAIP3, ITGA2, ABCC2, AIRE, IL6R/ST, LY96, AFF3, and TREX1—that may contribute to SSc susceptibility and clinical heterogeneity. Here, IRAK1 is linked to systemic sclerosis.