AbstractObjectiveTo investigate the role of the HO‐1 gene as a novel functional candidate gene for rheumatoid arthritis (RA).MethodsWe performed a case–control study including 736 RA patients and 846 healthy controls of Spanish Caucasian origin. Two putative functional HO‐1 promoter polymorphisms, a (GT)n microsatellite and a −413 A/T single‐nucleotide polymorphism (SNP), were selected as genetic markers and genotyped using polymerase chain reaction–based methods. In addition, the intracellular expression of heme oxygenase 1 (HO‐1) was determined in healthy individuals with different (GT)n genotypes.ResultsThe distribution of HO‐1 (GT)n short (S) alleles (≤25 GT repeats) and long (L) alleles (>25 GT repeats) revealed a significant protective effect of S (GT)n alleles (P = 0.019) (odds ratio [OR] 0.8, 95% confidence interval [95% CI] 0.7–0.9) and the SS (GT)n genotype (P = 0.002) (OR 0.6, 95% CI 0.4–0.9). In contrast, the −413 HO‐1 promoter SNP did not yield any statistically significant deviation between RA patients and controls, considering either allele or genotype frequencies. The haplotype analysis showed a strong protective effect of the S/A haplotype (P = 7 × 10−7, corrected P [Pcorr] = 3 × 10−6) (OR 0.4, 95% CI 0.3–0.6), whereas the L/A haplotype showed the opposite tendency (P = 0.008, Pcorr = 0.03) (OR 1.2, 95% CI 1.0–1.4). In addition, we demonstrated that monocytes from individuals carrying the SS (GT)n genotype showed a significantly higher percentage of HO‐1 expression than did cells from LL homozygous individuals (P = 0.0003).ConclusionIn this study, we identified the HO‐1 (GT)n microsatellite as a new genetic marker involved in RA genetics in our population.