GT-repeat polymorphism in the heme oxygenase-1 gene promoter and the risk of carotid atherosclerosis related to arsenic exposure

Abstract

BackgroundArsenic is a strong stimulus of heme oxygenase (HO)-1 expression in experimental studies in response to oxidative stress caused by a stimulus. A functional GT-repeat polymorphism in the HO-1 gene promoter was inversely correlated to the development of coronary artery disease in diabetics and development of restenosis following angioplasty in patients. The role of this potential vascular protective factor in carotid atherosclerosis remains unclear. We previously reported a graded association of arsenic exposure in drinking water with an increased risk of carotid atherosclerosis. In this study, we investigated the relationship between HO-1 genetic polymorphism and the risk of atherosclerosis related to arsenic.MethodsThree-hundred and sixty-seven participants with an indication of carotid atherosclerosis and an additional 420 participants without the indication, which served as the controls, from two arsenic exposure areas in Taiwan, a low arsenic-exposed Lanyang cohort and a high arsenic-exposed LMN cohort, were studied. Carotid atherosclerosis was evaluated using a duplex ultrasonographic assessment of the extracranial carotid arteries. Allelic variants of (GT)n repeats in the 5'-flanking region of the HO-1 gene were identified and grouped into a short (S) allele (< 27 repeats) and long (L) allele (≥ 27 repeats). The association of atherosclerosis and the HO-1 genetic variants was assessed by a logistic regression analysis, adjusted for cardiovascular risk factors.ResultsAnalysis results showed that arsenic's effect on carotid atherosclerosis differed between carriers of the class S allele (OR 1.39; 95% CI 0.86-2.25; p = 0.181) and non-carriers (OR 2.65; 95% CI 1.03-6.82; p = 0.044) in the high-exposure LMN cohort. At arsenic exposure levels exceeding 750 μg/L, difference in OR estimates between class S allele carriers and non-carriers was borderline significant (p = 0.051). In contrast, no such results were found in the low-exposure Lanyang cohort.ConclusionsThis exploratory study suggests that at a relatively high level of arsenic exposure, carriers of the short (GT)n allele (< 27 repeats) in the HO-1 gene promoter had a lower probability of developing carotid atherosclerosis than non-carriers of the allele after long-term arsenic exposure via ground water. The short (GT)n repeat in the HO-1 gene promoter may provide protective effects against carotid atherosclerosis in individuals with a high level of arsenic exposure.

Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease

“…The significant association of this polymorphism with cardiovascular outcome and mortality in patients with CAD also corroborated previous studies in these high-risk populations. [8][9][10][11][12][13][14][15][16] Ample evidence has shown the beneficial effect of HO-1 in experimental kidney disease, including ischemia-reperfusion kidney injury, nephrotoxin or angiotensin II-induced renal injury, kidney transplantation, and diabetic models. 2,18,22 Kim et al 23 demonstrated the renoprotective effect of HO-1 using its inducer and inhibitor through an antiapoptotic pathway in the unilateral ureteral obstruction (UUO) model.…”

“…7,8 Previous studies have demonstrated an increased susceptibility to cardiovascular events and increased mortality of longer (GT) n repeats in the HO-1 gene promoter in high-risk populations such as patients with diabetes mellitus, hypercholesterolemia, a history of smoking, peripheral artery disease, or arsenic exposure. [8][9][10][11][12][13][14][15][16] Our recent study also showed that longer (GT) n repeats in the HO-1 gene promoter were associated with a higher risk of long-term cardiovascular events and mortality in hemodialysis patients. 17 Until now, the investigations for this polymorphism were mostly restricted to graft survival in kidney transplant recipients.…”

Length Polymorphism in Heme Oxygenase-1 and Cardiovascular Events and Mortality in Hemodialysis Patients

“…In a longitudinal study, HO-1 promoter polymorphism influenced the occurrence of coronary events in patients with peripheral artery disease (10). Among arsenic-exposed individuals in Taiwan, the carriers of the short (GT) n polymorphisms in the HO-1 gene promoter had lower rates of CV mortality and hypertension and a lower probability of developing carotid atherosclerosis (11,27,28). With regard to ischemic cerebrovascular events, one study reported that patients with long (.26 GT) repeats in the HO-1 gene promoter had greater susceptibility for developing ischemic stroke in the presence of low HDL cholesterol (29).…”

Study of GT-repeat expansion in Heme oxygenase-1 gene promoter as genetic cause of male infertility

“…Several studies have demonstrated that the GT-repeats in the promoter region of HO-1 gene is highly polymorphic, modulated gene transcription by oxidant challenge, and associated with different diseases [1,12,14,25,26]. Recent studies indicated that oxidative stress has been implicated in the pathogenesis of male infertility [18][19][20]22].…”

“…The GT-repeats in heme oxygenase-1 gene promoter is highly polymorphic and modulates gene expression levels by oxidant challenge [10]. Its polymorphism has been reported to show relationship with some oxidative dependent diseases such as cardiovascular, diabetes and different kind of cancers [11][12][13][14]. Its expression is related to the number of the GT-n repeats in the promoter region of HO-1 gene [11,12].…”