Genetic analysis of rheumatoid arthritis in familial cases: implications for future research

Objective. Rheumatoid arthritis (RA) is a systemic autoimmune disorder influenced by complex genetic and environmental factors. While several genetic loci have been associated with RA in European and East Asian populations, there is limited evidence from South Indian cohorts. This study aimed to identify potentially relevant genetic variants that co-segregate with the RA phenotype within South Indian multiplex families. Materials and methods. A family-based case series was conducted over 18 months, enrolling 23 individuals from seven South Indian families with multiple affected members. WES was performed, and variants were annotated using multiple bioinformatics databases and pathogenicity prediction tools. Rigorous filtering strategies were applied to exclude common variants, and correlations were explored between genetic findings and clinical features, including autoantibody status, synovitis, erosive disease, and therapeutic response. Ethical approval and informed consent were obtained for all participants. Results. Pathogenic and likely pathogenic variants were identified in immune-regulatory genes such as HLA-DPB1 (DPB1*04:02 allele), TNF, CTRP6, FCGR2A, FCGR3A, and MTHFR. These variants were observed in individuals with high anti-citrullinated protein antibody titers, female predominance, severe synovitis, and early erosive disease. CTRP6 variants suggest a possible involvement of complement pathway regulation, which requires functional validation. Pharmacogenetic variants were identified that may have potential relevance to drug metabolism and treatment response. Asymptomatic carriers of RA-associated mutations indicated incomplete penetrance and possible protective modifiers. Conclusion. This exploratory study identifies established and novel genetic variants observed in familial RA cases, which may contribute to disease mechanisms and warrant validation in larger cohorts. The findings underscore the importance of population-specific genetic profiling for improving disease understanding and risk stratification. Incorporating pharmacogenetic markers into treatment planning may be considered in future validated settings, but clinical applicability remains to be established.