AbstractThe study was conducted to investigate the frequency of three gene polymorphisms in the 3′‐untranslated region (3′‐UTR) of human leucocyte antigen‐G (HLA‐G) gene in south Indian patients with rheumatoid arthritis (RA) and analyze their influence on disease susceptibility, phenotype and treatment response. HLA‐G 14 bp insertion (Ins)/deletion (del) (rs66554220), HLA‐G +3142G>C (rs1063320) and +3187A>G (rs9380142) polymorphism was analyzed in 221 RA patients and 200 healthy controls. Frequency of HLA‐G genotypes or alleles did not differ between patients and controls. Analysis based on rheumatoid factor (RF) status revealed that the frequency of allele ‘A’ (rs9380142) was significantly higher in RF‐positive than in RF‐negative patients [84% vs 74%, Yates‐corrected P value (Pc) = 0.04, odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.0–3.2]. A similar difference was maintained in RF‐positive female patients than their RF‐negative counterparts (83% vs 71%, Pc = 0.02, OR = 1.9, 95% CI = 1.0 to 3.4) and between RF‐positive and RF‐negative young onset RA (YORA) patients (84% vs 73%, Pc = 0.03, OR = 1.9, 95% CI = 1.0–3.2), suggesting that rs9380142 polymorphism influenced RF status. The 14 bp Ins allele of rs66554220 was significantly more prevalent in RF‐positive YORA than in RF‐positive late onset RA (LORA) patients (51% vs 25%, P = 0.03, OR = 3.1, 95% CI = 1.1–9.8). Frequency of the four major haplotypes [InsGA (48%), DelGA (22%), DelCG (18%), DelCA (9.7%)] observed did not differ between cases and controls. HLA‐G does not appear to be a risk factor for development of RA in south Indian Tamils but may act as a genetic modifier of clinical phenotype in terms of autoantibody production, gender preference and age at disease onset.