Microsatellite polymorphism in heme oxygenase-1 gene promoter is associated with susceptibility to oxidant-induced apoptosis in lymphoblastoid cell lines

Abstract

Heme oxygenase-1 (HO-1) confers cytoprotection against oxidative stress. A (GT)n dinucleotide repeat in the 5-flanking region of human HO-1 gene shows length polymorphism, which was classified into S (< 27 GT), M (27-32 GT), and L alleles (> 33 GT). Polymorphism in the HO-1 gene promoter was shown to be associated with susceptibility to pulmonary emphysema and restenosis after angioplasty. However, the biologic mechanism underlying these associations is still unclear. To examine this issue, we established lymphoblastoid cell lines (LCLs) from subjects possessing S/S or L/L genotypes. HO-1 mRNA expressions and HO activities induced by oxidative stress were significantly higher in LCLs with S/S than those with L/L. Furthermore, LCLs with S/S were significantly more resistant to oxidant-induced apoptosis than those with L/L. These findings suggested that the polymorphism of the HO-1 gene is associated with the strength of antiapoptotic effects of HO-1, resulting in an association with susceptibility to oxidative stress-mediated diseases.

Reduced Expression of Heme Oxygenase-1 in Patients with Coronary Atherosclerosis

“…In the present study, we tested the hypothesis that individual capacity to upregulate HO-1 is genetically determined and that reduced HO-1 expression may contribute to the development of coronary atherosclerosis. Consistent with the notion that transcriptional activity of the HO-1 gene decreases with increasing numbers of (GT)n repeats (36), patients with the L/ L genotype in the present study showed a lower level of ΔHO-1 mRNA than patients carrying other genotypes, indicating that the capacity for HO-1 upregulation is, at least in part, genetically regulated. Consistent with this notion, the ΔHO-1 mRNA results were reproducible (the CV was 7.2%).…”

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation

“…Both can alter the basal level of HO-1 expression as well as in response to stressors (32). Individuals with short (GT)n repeat lengths are "high" HO-1 expressors compared to those individuals with long (GT)n) repeats (33). Several studies indicate that the ability to upregulate HO-1 expression is an important protective factor in some diseases (e.g., cardiovascular disease and renal transplantation) (32).…”

Increased risk of venous thromboembolism is associated with genetic variation in heme oxygenase-1 in Blacks

“…DNA polymorphisms which impair or reduce HO-1 response may therefore lead to increased risk of endothelial dysfunction and vascular disease, including resolution of venous thrombosis [14]. Human patients with shorter HMOX1 promoter (GT) n repeat alleles might benefit by having a stronger inducible heme oxygenase response [15,26], and indeed, long alleles were associated with increased risk of recurrent VTE in the only other study to date to examine the role of this polymorphism in VTE [16].…”

“…Findings from recent studies indicate that 50-73% of patients with VTE presented in an outpatient setting [28,29]; therefore our findings are only representative of individuals with VTE severe enough to require hospitalization. Finally, although longer HMOX1 (GT) n promoter repeats have been associated with impaired inducible heme oxygenase [15,27,30], no functional measurements of expression levels or enzyme activity were available in our patient samples.…”

“…Knockout mice which do not express HO-1 have been shown to have an enhanced inflammatory response and significantly impaired resolution of experimentally induced venous thrombosis [14]. Humans carry a (GT) n microsatellite (rs3074372) located in the promoter of the heme oxygenase-1 (HMOX1) gene that may influence the level of HO-1 response whereby individuals with lower numbers of repeats have higher inducible expression [15]. Indeed, Austrian VTE patients who carried longer HMOX1 (GT) n repeat lengths have been reported to be at an increased risk of recurrence [16].…”