To investigate the role of the HO-1 gene as a novel functional candidate gene for rheumatoid arthritis (RA).
We 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.
The distribution of HO-1 (GT)(n) short (S) alleles (< or =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 x 10(-7), corrected P [P(corr)] = 3 x 10(-6)) (OR 0.4, 95% CI 0.3-0.6), whereas the L/A haplotype showed the opposite tendency (P = 0.008, P(corr) = 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).
In this study, we identified the HO-1 (GT)(n) microsatellite as a new genetic marker involved in RA genetics in our population.