HO‐1 promoter polymorphism associated with rheumatoid arthritis

Objective To investigate the role of the HO‐1 gene as a novel functional candidate gene for rheumatoid arthritis (RA). Methods 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)...

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Published in:Arthritis and rheumatism 2007-12, Vol.56 (12), p.3953-3958
Main Authors: Rueda, Blanca, Oliver, Javier, Robledo, Gema, López‐Nevot, Miguel A., Balsa, Alejandro, Pascual‐Salcedo, Dora, González‐Gay, Miguel A., González‐Escribano, Maria F., Martín, Javier
Format: Article
Language:English
Subjects:
Adult
Aged
Arthritis, Rheumatoid - genetics
Biological and medical sciences
Case-Control Studies
Diseases of the osteoarticular system
Female
Genetic Markers - genetics
Genetic Predisposition to Disease
Genotype
Haplotypes
Heme Oxygenase-1 - genetics
Humans
Inflammatory joint diseases
Male
Medical sciences
Microsatellite Repeats - genetics
Middle Aged
Polymorphism, Single Nucleotide - genetics
Promoter Regions, Genetic - genetics
Severity of Illness Index
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Summary:Objective To investigate the role of the HO‐1 gene as a novel functional candidate gene for rheumatoid arthritis (RA). Methods 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. Results The 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). Conclusion In this study, we identified the HO‐1 (GT)n microsatellite as a new genetic marker involved in RA genetics in our population.
ISSN:0004-3591
1529-0131
DOI:10.1002/art.23048