Summary Background Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease characterized by clinical and molecular heterogeneity, notably in the presence of anti‐cyclic citrullinated peptide antibodies (CCP). CCP‐positive (CCP+) RA patients exhibit more severe disease progression and distinct treatment responses compared to CCP‐negative (CCP‐) patients. Although previous studies have investigated cellular and molecular differences between these subtypes, their genetic differences are understudied. Methods We leveraged the RACER (Rheumatoid Arthritis Comparative Effectiveness Research) cohort, comprising 555 CCP+/RF+ and 384 CCP‐/RF+ RA patients. Using a novel framework, we integrated a network‐based genome‐wide association study (GWAS) with multi‐omic data to uncover corresponding genetic and molecular differences. Findings We uncovered a significant heritability difference between these disease groups. Network‐based GWAS uncovered 14 putative gene modules, including many genes outside the HLA loci, that explained genetic differences between CCP+/RF+ and CCP‐/RF+ RA. Heritability partitioning and multivariate expression analyses validated 4 modules, highlighting novel genetic loci underlying phenotypic differences. Module functional significance was established using multiple orthogonal cohorts, underscoring their biological relevance. Interpretation Our findings demonstrate the utility of network‐based approaches in revealing differential genetic risk factors underlying CCP+/RF+ and CCP‐/RF+ RA. Disease‐associated gene modules detected in synovial tissue were also observed in peripheral blood, indicating joint‐specific molecular programs are reflected systemically. This cross‐tissue concordance highlights the potential for blood‐based assays to capture pathogenic mechanisms active in the joints, enabling practical patient stratification. Our findings highlight why CCP+/RF+ and CCP‐/RF+ RA patients exhibit distinct clinical courses and therapeutic responses, supporting precision‐guided treatment strategy development in RA.
Rahimikollu et al. (Wed,) studied this question.