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In this study, we sought to investigate the genetic influence of two HLA-G 3'-untranslated region (3'-UTR) polymorphisms - 14 bp (rs66554220) and +3142C>G (rs1063320) and their compounding haplotypes in susceptibility to rheumatoid arthritis (RA) in a two-region Brazilian study comprising of 539 patients and 489 controls. All subjects were polymerase chain reaction (PCR) genotyped for the referred polymorphisms and logistic regression models controlling for sex, city and age were performed. Homozygozity for the +3142G allele was associated with an increased risk of RA [odds ratio (OR) = 1.45, 95% confidence interval (CI) = 1.075-1.959, P(Bonf)  = 0.030], whereas no association was observed for the 14 bp polymorphism. Haplotype comparisons between patients and controls showed a decreased frequency of the delC haplotype in patients (OR = 0.70, 95% CI = 0.521-0.946, P(Bonf)  = 0.040), which remained significant in the rheumatoid factor (RF)-positive group (OR = 0.66, 95% CI = 0.482-0.900, P(Bonf)  = 0.018), but not in the RF-negative group. These results corroborate the hypothesis of an involvement of HLA-G in the susceptibility of RA. The +3142G allele is associated with haplotype lineages that share high identity and are regarded as low producers. The presence of the G allele in homozygosis could be responsible for a low HLA-G expression profile that could favor the triggering of RA., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)