Shorter GT repeat polymorphism in the heme oxygenase-1 gene promoter has protective effect on ischemic stroke in dyslipidemia patients

Bai, Chyi Huey; Chen, Jiunn Rong; Chiu, Hou Chang; Chou, Chia Chi; Chau, Lee‐Young; Pan, Wen Harn

doi:10.1186/1423-0127-17-12

Cited by 27 publications

(22 citation statements)

References 40 publications

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“…Of these, three large studies 15–17 , including 1800 to 3000 patients, found no relationship between HO-1 VNTR repeat length and their primary endpoints restenosis 15,17 or coronary artery disease 16 , but a large number of smaller studies did.Putting these data in perspective with our study, it should be considered that HO-1 induction occurs in response to stress conditions 10,11,18 , and a more severe deficit in HO-1 might be necessary in the general (low-risk) population to evoke deleterious effects, whereas a less severe deficit could suffice in higher-risk patients. This interpretation is consistent with several reports that found an association between HO-1 VNTR length and vascular endpoints only in high-risk sub groups such as diabetic subjects or smokers 11,13,19,20 .…”

Section: Discussionsupporting

confidence: 93%

Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular Disease

Pechlaner

Willeit

Summerer

et al. 2015

ATVB

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Objective The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat (VNTR) polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease (CVD). We examined this association prospectively in the general population. Approach and Results Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 VNTR length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared to the rest of the population (recessive trait) featured substantially increased CVD risk (hazard ratio [95% confidence interval], 5.45 (2.39, 12.42); P<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] vs. 0.0 [0.0, 2.2] mm; P=0.0012), and a trend towards higher levels of oxidised phospholipids on apoB-100 (median OxPL/apoB level [interquartile range], 11364 [4160, 18330] vs. 4844 [3174, 12284] relative light units; P=0.0554). Increased CVD risk in those homozygous for ≥32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (HR [95% CI], 3.26 [1.50, 7.33]; P=0.0043). Conclusions This study found a strong association between the HO-1 VNTR polymorphism and CVD risk confined to subjects with a high number of repeats on both HO-1 alleles, and provides evidence for accelerated atherogenesis and decreased anti-oxidant defence in this vascular high-risk group.

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Section: Discussionsupporting

confidence: 93%

Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular Disease

Pechlaner

Willeit

Summerer

et al. 2015

ATVB

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“…In two previous studies conducted in Japan (279 controls and 298 CHD patients) (Kaneda et al 2002) and Taiwan (322 controls and 664 CHD patients) ), significant associations were found between HO-1 gene promoter polymorphism and CHD risk in subjects with one of the CHD risk factors; another study (Bai et al 2010) also found that (GT) n repeats in HO-1 gene promoter may affect cerebral ischemic risk in dyslipidemia patients. Our study is broadly consistent with these results, however, we further demonstrated for the first time that this association may be attributed to the interaction between HO-1 gene promoter and OS.…”

Section: Discussionmentioning

confidence: 89%

Short (GT) repeats in heme oxygenase-1 gene promoter are associated with lower risk of coronary heart disease in subjects with high levels of oxidative stress

Zhou

Ding

et al. 2012

Cell Stress and Chaperones

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Although (GT) ( n ) repeats in heme oxygenase-1 (HO-1) promoter may modulate gene transcriptional activity, the association between (GT) ( n ) repeats polymorphism and risk of coronary heart disease (CHD) from different levels of oxidative stress (OS) is unknown. We determined the allelic frequencies of (GT) ( n ) repeats in the HO-1 gene promoter and plasma malonaldehyde (MDA) as biomarkers of OS in 2,298 pairs of CHD patients and controls in the Chinese population. Furthermore, we measured MDA in culture mediums and HO-1 expressions levels in cell lysates of endothelial cells carrying various (GT) ( n ) genotypes under different concentrations of H(2)O(2). Compared with L/L genotype (>25 repeats) carriers, the adjusted odd ratios for S/S genotype (≤25 repeats) in subjects with different levels of OS (MDA < 1.83, 1.83-2.91, >2.91 μmol/L) were 1.06 (95%CI, 0.75 to 1.49), 0.79 (95%CI, 0.55 to 1.12), and 0.60 (95%CI, 0.44 to 0.81), respectively (P (interaction) = 0.002). In biological experiments, compared with endothelial cells carrying L/L genotype, cells with S/S genotype did not have a significantly higher HO-1 expression under 0 μmol/L H(2)O(2), but displayed a significantly higher HO-1 expression under 50 μmol/L H(2)O(2) (P (interaction) = 0.003). S/S genotype in HO-1 gene promoter is associated with a lower risk of CHD in subjects with higher levels of OS, because under conditions of high OS, the S/S genotype has higher levels of HO-1, an antioxidant.

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“…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). Our finding corroborates the concept that the polymorphism of HO-1 is associated with CVD risk in the high-risk population; patients with CKD, especially ESRD on chronic HD, are definitely a highrisk population for CVD.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Hung

Tarng

2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Persistent inflammation and oxidative stress play a pathogenic role in the high cardiovascular morbidity and mortality of hemodialysis patients. Heme oxygenase-1 is considered to have antiinflammatory and antioxidant properties. This study assessed the association between the length of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene microsatellite promoter and cardiovascular events and mortality among hemodialysis patients.Design, setting, participants, & measurements Study participants were recruited from October 1, 2006 to December 31, 2006. The allelic frequencies of the length of guanosine thymidine dinucleotide repeats (the S allele represents shorter [,27] repeats, and the L allele represents longer [$27] repeats) in the heme oxygenase-1 gene promoter were analyzed in 1080 unrelated chronic hemodialysis patients and 365 healthy controls for distribution comparison. Cardiovascular events and mortality were the study outcomes, and the hemodialysis patients were followed until June 30, 2011.Results The genotype proportions were 20.6%, 48.8%, and 30.6% for S/S, S/L, and L/L, respectively, in the hemodialysis patients and comparable with those proportions in healthy controls. The patients with the L/L genotype had significantly higher baseline serum high-sensitivity C-reactive protein and malondialdehyde levels than the patients with the S/S or S/L genotypes. During a median follow-up of 50 months, 307 patients died. A Kaplan-Meier survival analysis showed the highest cardiovascular events and all-cause mortality in patients with the L/L genotype. The adjusted hazard ratios (95% confidence intervals) for each L allele in additive model were 1.42 (1.20 to 1.67 [P,0.001]) for cardiovascular events and 1.19 (1.01 to 1.40 [P=0.03]) for all-cause mortality.Conclusions Chronic hemodialysis patients with longer lengths of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter exhibit higher inflammation and oxidative stress. These patients have higher risk of long-term cardiovascular events and mortality.

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Shorter GT repeat polymorphism in the heme oxygenase-1 gene promoter has protective effect on ischemic stroke in dyslipidemia patients

Cited by 27 publications

References 40 publications

Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular Disease

Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular Disease

Short (GT) repeats in heme oxygenase-1 gene promoter are associated with lower risk of coronary heart disease in subjects with high levels of oxidative stress

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

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