Interactive effect of the glutathione S-transferase genes and cigarette smoking on occurrence and severity of coronary artery risk

Cardiovascular diseases and cancer are the main causes of death in developed countries. Mortality trends for these diseases suggest that they share common pathogenetic mechanisms. Glutathione S-transferase (GST) is a family of enzymes that detoxify reactive electrophiles, particularly present in tobacco smoke. Glutathione S-transferase null M1 and T1 (GSTM1 and GSTT1) genotypes have often been associated with increased risk of developing cancer. Our hypothesis was that the polymorphic GSTM1 and GSTT1 genes modulate the risk of smoking-coronary artery disease (CAD). We evaluated the distribution of GST genotypes in 430 angiographically defined patients (308 CAD and 122 non-CAD). The frequencies of GST null genotypes did not differ significantly between patients with CAD and without CAD. However, smokers with GSTM1 and GSTT1 null genotypes had a significantly higher risk of CAD than never-smokers with these genotypes present (OR 2.2 and 3.4 for smokers with null GSTM1 and GSTT1 genes, respectively). There was also evidence of multiple interaction between GSTM1 and GSTT1 deleted genotypes and smoking. In nonsmokers carrying both null genotypes the risk of CAD was 0.66. In smokers with both present genotypes the OR was 1.5 and was significantly increased in smokers with concurrent lack for GSTM1 and GSTT1 genes (OR=4.0). Moreover, smokers lacking GST genes had both more stenosed vessels and a higher Duke score than smokers expressing the genes. We also examined the levels of DNA damage in 66 men patients using the micronucleus test, a sensitive assay for evaluating chromosome damage. Micronucleus levels were higher in smokers with null genes than in smokers with present genes. These observations suggest that GST-null genotypes strengthen the effect of smoking on CAD risk by modulating the detoxification of genotoxic atherogens.     

Association between Glutathione S-Transferase T1, M1, and P1 Genotypes and the Risk of Colorectal Cancer

Glutathione S-transferases (GSTs) are enzymes which play an important role in the neutralization of toxic compounds and eradication of electrophilic carcinogens. Genetic polymorphisms within the genes encoding for GSTs may therefore cause variations in their enzyme activity, which may in turn influence the interindividual susceptibility to cancers. In this study, we aimed to investigate the association between genetic polymorphisms of GSTT1, GSTM1, and GSTP1 and the risk of colorectal cancer (CRC) in 264 cases and 317 controls in a Chinese population. Genotyping was performed by using multiplex PCR (for GSTT1 and GSTM1) and PCR-RFLP (for GSTP1) methods. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Our results showed that individuals with GSTT1 and GSTM1 null genotypes exhibited a higher risk of CRC (GSTT1, OR,1.66; 95% CI, 1.20-2.31, P=0.003; GSTM1, OR,1.57; 95% CI,1.13-2.18, P=0.007), while no association was observed for GSTP1 (P_heterozygous=0.790 or P_variant=0.261). Furthermore, individuals who simultaneously carried the null genotypes for both GSTT1 and GSTM1 showed a stronger risk association (OR, 1.95; 95% CI, 1.33-2.85; P<0.001). In conclusion, the GSTT1 and GSTM1 polymorphisms, but not GSTP1, may modulate the CRC risk among Chinese.

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Functional polymorphisms in the LTF gene and risk of coronary artery stenosis

Plasma lactoferrin concentrations are increased in patients with coronary artery stenosis. We investigated the effects of LTF gene polymorphisms in 305 healthy blood donors and their associations with coronary artery stenosis in 236 patients admitted for coronary angiography. Lactoferrin concentrations were determined by enzyme immunoassay. Genotyping was performed by polymerase chain reaction and DNA sequencing of LTF exons 2 and 4. In the blood donors, the deletion variant of rs10662431 and the G allele of rs1126478 were associated with higher plasma lactoferrin concentrations. The G allele of rs1126478 was more frequent in patients with significant coronary artery stenosis (p = 0.018, p value limit for significance by permutation = 0.030). The association remained significant in logistic regression with adjustment for clinical risk factors (odds ratio 2.485 [95% confidence interval 1.116-5.536], p = 0.026), but was weakened upon the inclusion of plasma lactoferrin (odds ratio 2.295 [0.949-5.550], p = 0.064). Current evidence indicates that rs1126478 affects the antibacterial effect of lactoferrin and that lactoferrin is involved in lipid metabolism. The relationships among lactoferrin genotypes, lactoferrin concentrations, and clinical factors on the risk for atherosclerosis are not fully understood, but the G allele of rs1126478 seems to have a detrimental effect in a European population.     

GSTM1, GSTT1 and GSTP1 polymorphisms in the Korean population

The isoenzymes of the glutathione s transferase (GST) family play a vital role in phase II of biotransformation of many substances. Using a multiplex polymerase chain reaction and a direct sequencing analysis, the frequencies of GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated in 1,051 Korean male subjects. We found that 53.8% of the individuals had the GSTM1 null genotype and 54.3% had the GSTT 1 null genotype. The genotypic distribution of GSTP1 was Ile105/Ile105 in 68.4%, Ile105/Val105 in 29.1% and Val105/Va105 in 2.5%. The most frequently observed combination of GSTM1, GSTP1 and GSTT1 genotypes was Null type/Ile105/Ile105/Null type, while the combination of Non-null type/Val105/Val105/Non-Null type was not observed. We found that the genotype distributions of three GST isoenzymes in the Koreans are similar to those reported in Asians and previously reported Koreans. We believe our results, which are represented by a large population, are reliable estimates of the frequencies of the polymorphic GST alleles in the Koreans and will help future researches on GST polymorphisms.     

Genetic polymorphism of the glutathione S-transferase M1 and T1 genes in three distinct Arab populations

Deletion polymorphisms for the glutathione S-transferase (GST) gene are associated with increased risk of cancer, and are implicated in detoxifying mutagenic electrophilic compounds. GST Polymorphic variants were reported for different populations. The aim of this study was to investigate the frequencies of GSTM1 and GSTT1 null genotypes among Bahraini, Lebanese and Tunisian Arabs. GST genotyping was done by multiplex PCR-based methods. Study subjects comprised 167 Bahrainis, 141 Lebanese and 186 Tunisians unrelated healthy individuals. GSTM1 deletion homozygosity of 49.7%, 52.5% and 63.4% were recorded for Bahraini, Lebanese and Tunisians, respectively. Among Bahrainis, the prevalence of GSTT1 null homozygotes was 28.7%, while in higher rates were seen in Lebanese (37.6%) and Tunisians (37.1%). Our results indicate that there are no major differences in allelic distribution of GSTM1 and GSTT1 genes between the three Arab populations investigated except between Bahrainis and Tunisians regarding the allelic distribution of GSTM1 gene (P=0.013). Combined analysis of both genes revealed that 14.4% of Bahrainis, 16.3% of Lebanese and 21.0% of Tunisians harbor the deleted genotype of both genes. This is the first study that addresses GST gene polymorphism in Bahraini and Lebanese Arabs, and will help genetic studies on the association of GSTM1 and GSTT1 polymorphisms with disease risks and drug effects in Arab populations.     

Association between glutathione S-transferase gene M1 and T1 polymorphisms and chronic obstructive pulmonary disease risk: A meta-analysis

Chronic obstructive pulmonary disease (COPD) is a severe lung disease characterized by long-term breathing problems. A series of studies have indicated that the glutathione S-transferase genes M1 and T1 are associated with COPD susceptibility; however, the result still remains inconclusive. This meta-analysis was performed to estimate the effect of GSTM1 and GSTT1 polymorphisms in COPD risk. Eligible case-control studies published between January 2000 and December 2017 was searched and retrieved. A total of 37 articles were screened out, including 4674 COPD patients and 5006 controls. Overall, our results found that GSTM1 and GSTT1 null genotypes significantly increased the risk of COPD (GSTM1: odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.31-1.77, P <.00001; GSTT1: OR = 1.28, 95% CI = 1.09-1.50, P = .003). Subgroup analysis by ethnicity suggested that there was a close association between GSTM1 null polymorphism and COPD susceptibility in each studied ethnicity, while GSTT1 null polymorphism only showed association with Asian COPD patients. Moreover, we also found that joint GSTM1/GSTT1 null genotypes showed a high association with increased COPD susceptibility (OR = 1.42, 95% CI = 1.21-1.66, P < .0001). In conclusion, our results indicated that GSTM1 null, GSTT1 null, and the combined GSTM1/GSTT1 null genotypes might be risk factors in the development of COPD. However, future case-control studies with large-scale participants are still required to further estimate these associations.     

广东地区汉族人群的hGSTP1Ile105Val基因多态性的研究

目的:对广东地区汉族人群的hGSTP1Ile105Val基因多态性进行研究。方法:应用PCR-RFLP(基因体外扩增限制性片段长度多态性分析)的技术方法进行研究。结果:该人群中GSTP1基因在105位点的野生型纯合子(AA)基因型的分布频率为57.4%,突变型纯合子(GG)基因型为6.7%,杂合子(AG)基因型为35.9%。结论:GSTP1纯合突变基因型在广东地区汉族人群中的分布频率为6.7%。     

Impact of renin-angiotensin-aldosterone system gene polymorphisms on left ventricular dysfunction in coronary artery disease patients

Background: Left ventricular dysfunction (LVD), followed by fall in cardiac output is one of the major complications in some coronary artery disease (CAD) patients. The decreased cardiac output over time leads to activation of the renin-angiotensin-aldosterone system which results in vasoconstriction by influencing salt-water homeostasis. Therefore, the purpose of the present study was to explore the association of single nucleotide polymorphisms (SNPs) in angiotensin I converting enzyme; ACE (rs4340), angiotensin II type1 receptor; AT1 (rs5186) and aldosterone synthase; CYP11B2 (rs1799998) with LVD. Methods and results: The present study was carried out in two cohorts. The primary cohort included 308 consecutive patients with angiographically confirmed CAD and 234 healthy controls. Among CAD, 94 with compromised left ventricle ejection fraction (LVEF ≤ 45) were categorized as LVD. The ACE I/D, AT1 A1166C and CYP11B2 T-344C polymorphisms were determined by PCR. Our results showed that ACE I/D was significantly associated with CAD but not with LVD. However, AT1 1166C variant was significantly associated with LVD (LVEF ≤ 45) (p value=0.013; OR=3.69), but CYP11B2 (rs1799998) was not associated with either CAD or LVD. To validate our results, we performed a replication study in additional 200 cases with similar clinical characteristics and results again confirmed consistent findings (p value=0.020; OR=5.20). Conclusion: AT1 A1166C plays important role in conferring susceptibility of LVD.     

非体外循环下冠状动脉旁路移植围术期血浆脑钠肽释放及其相关性研究

背景：B型脑钠肽已成为心血管疾病诊断重要的血清标志物,作为心血管疾病危险因素分层的重要因子。 目的：分析冠状动脉旁路移植前后B型脑钠肽与各项血流动力学参数的关系。 方法：选择30例冠心病行冠脉旁路移植患者,分为左室射血分数≥ 50%心功能正常患者13例;左室射血分数< 50%心功能不全患者17例。观察患者移植前1 d、移植后7 h、移植后1,3,5,7 d血浆B型脑钠肽水平变化趋势,分析移植前后B型脑钠肽与心功能各项指标的相关关系。 结果与结论：左室射血分数≥ 50%组患者冠脉旁路移植前后血浆B型脑钠肽水平显著低于左室射血分数< 50%组;组内比较移植后血浆B型脑钠肽水平均显著高于移植前(P < 0.05或P < 0.001)。患者冠脉旁路移植前B型脑钠肽水平与纽约心脏病协会心功能分级、左房内径、左室内径呈正相关(r=0.61;r=0．34;r=0．67);与左室射血分数、心排血量呈负相关(r=-0.75;r=-0.70)。患者移植后B型脑钠肽峰值浓度与出院前纽约心脏病协会心功能分级、超声心动图左室舒张末期内径、肺动脉压力呈正相关(r=0.72;r=0.70;r=0.45)。结果说明冠心病患者冠脉旁路移植前血浆B型脑钠肽质量浓度与左心室射血分数及左心室舒张末期内径有很好的相关性,能准确反映冠脉旁路移植前后的心功能状态。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Polymorphism of glutathione S-transferase M1 and T1 gene LOCI in COPD

Chronic obstructive pulmonary disease (COPD) is a complex combination of signs and symptoms in patients with chronic bronchitis and emphysema, diseases that largely result from cigarette smoking. A little information is available for the underlying molecular mechanisms that are responsible for its occurrence. Polymorphisms in genes of xenobiotics metabolizing enzymes are expected to modulate individual responses to genotoxic carcinogens. Present study was a case–control study of COPD patients and healthy controls. Genetic polymorphisms of GSTM1 and GSTT1 genes in 50 COPD patients and 50 healthy controls were investigated using multiplex polymerase chain reaction–restriction fragment length polymorphism techniques to determine whether polymorphisms of these genes are linked to genetic susceptibility to COPD. All subjects were males and smokers. The frequency of GSTM1 homozygous null genotype was 28.0% in COPD cases when compared with controls (32.0%). The difference was not significant showing that risk of COPD was not associated with the GSTM1 null genotypes. The frequencies of homozygous null genotypes of GSTT1 were significantly higher in COPD cases as compared with controls (40% versus 14.0%) suggesting that the theta-glutathione S-transferases null genotype may be associated with the susceptibility to COPD. No significant differences were observed when comparisons were performed according to severity of disease and smoking for GSTM1 and GSTT1. It was also observed that COPD developed in the early age and with a shorter pack-year history in Indian population.     

Effect of continuous and interval exercise training on the PETCO2 response during a graded exercise test in patients with coronary artery disease

OBJECTIVE:

The purpose of this study was to evaluate the following: 1) the effects of continuous exercise training and interval exercise training on the end-tidal carbon dioxide pressure (PETCO₂) response during a graded exercise test in patients with coronary artery disease; and 2) the effects of exercise training modalities on the association between PETCO₂ at the ventilatory anaerobic threshold (VAT) and indicators of ventilatory efficiency and cardiorespiratory fitness in patients with coronary artery disease.

METHODS:

Thirty-seven patients (59.7±1.7 years) with coronary artery disease were randomly divided into two groups: continuous exercise training (n = 20) and interval exercise training (n = 17). All patients performed a graded exercise test with respiratory gas analysis before and after three months of the exercise training program to determine the VAT, respiratory compensation point (RCP) and peak oxygen consumption.

RESULTS:

After the interventions, both groups exhibited increased cardiorespiratory fitness. Indeed, the continuous exercise and interval exercise training groups demonstrated increases in both ventilatory efficiency and PETCO₂ values at VAT, RCP, and peak of exercise. Significant associations were observed in both groups: 1) continuous exercise training (PETCO₂VAT and cardiorespiratory fitness r = 0.49; PETCO₂VAT and ventilatory efficiency r = -0.80) and 2) interval exercise training (PETCO₂VAT and cardiorespiratory fitness r = 0.39; PETCO₂VAT and ventilatory efficiency r = -0.45).

CONCLUSIONS:

Both exercise training modalities showed similar increases in PETCO₂ levels during a graded exercise test in patients with coronary artery disease, which may be associated with an improvement in ventilatory efficiency and cardiorespiratory fitness.     

Association of GST M1 null polymorphism with Parkinson's disease in a Chilean population with a strong Amerindian genetic component

We have studied the association of a null mutation of Glutathione Transferase M1 (GST M1*0/0) with Parkinson's disease (MIM 168600) in a Chilean population with a strong Amerindian genetic component. We determined the genotype in 349 patients with idiopathic Parkinson's disease (174 female and 175 male; 66.84+/-10.7 years of age), and compared that to 611 controls (457 female and 254 male; 62+/-13.4 years of age). A significant association of the null mutation in GST M1 with Parkinson's disease was found (p=0.021), and the association was strongest in the earlier age range. An association of GSTM1*0/0 with Parkinson's disease supports the hypothesis that Glutathione Transferase M1 plays a role in protecting astrocytes against toxic dopamine oxidative metabolism, and most likely by preventing toxic one-electron reduction of aminochrome.     

GSTM1 and GSTP1 polymorphisms as potential factors for modifying the effect of smoking on inflammatory response

Inflammation has been known to be an important underlying condition for development of various diseases including cancer. The aims of this study were to investigate whether tobacco smoke exposure increases the level of inflammation biomarkers and the GSTM1 and GSTP1 gene polymorphisms are associated with inflammatory response due to tobacco smoke exposure. We measured urinary cotinine level in 300 healthy university students. Total serum TNF-alpha levels and blood WBC counts were determined to evaluate inflammatory response. Allelic loss of the GSTM1 and the GSTP1 (Ile105Val) polymorphism were determined by PCR and RFLP. Tobacco smoke exposure was found to be associated with increase of both TNF-alpha level and WBC count. Particularly, smokers with combination of GSTM1 null and GSTP1 AG or GG genotypes showed higher TNF-alpha level than those with the other genotype combinations (p=0.07). This result suggests that smoking may induce inflammation measured as TNF-alpha level or WBC count and combinations of the GSTM1 and GSTP1 polymorphisms may modify the effect of smoking on serum TNF-alpha level.     

Interactions between rs5498 polymorphism in the ICAM1 gene and traditional risk factors influence susceptibility to coronary artery disease

Coronary artery disease (CAD) depends on multiple genetic and environmental factors. Adhesion molecules are markers of endothelium dysfunction. Intercellular adhesion molecule-1 (ICAM-1) interacts with leukocyte integrins and promotes atherosclerotic process at the surface of endothelial cells. The aim of the study was to assess the association between ICAM1 rs5498 polymorphism and CAD and to establish whether there are any interactions between this polymorphism and traditional risk factors in determining the risk of CAD. We studied 191 cases with angiographically documented CAD and 203 controls with no signs of cardiovascular diseases. The ICAM1 polymorphism was genotyped using PCR–RFLP method. Data were analyzed with the STATISTICA 7.1 and EpiInfo 6 softwares. We did not observe significant differences in the distribution of genotypes and alleles of rs5498 between cases and controls. We only found a tendency to a higher prevalence of G allele carriers (AG + GG) in patients compared to controls (68 vs. 64%, P = 0.399). A synergistic effect of G allele carrier-state and smoking that had influenced the risk of CAD [synergy index multiplicative (SIM = 2.09)] was observed. Smoking carriers of G allele compared to non-smoking AA were more prevalent in CAD group (39.8%) than among controls (13.3%, P < 0.0001, OR 4.81). Moreover, there was also a synergistic effect between G allele carrier-state and an elevated level of triacylglycerols (TG) (SIM = 1.28) increasing the risk of CAD. There is a synergistic interaction between rs5498 genotype and smoking that increases the risk of CAD.     

脂联素基因SNP+45 T/G单核苷酸多态性与冠心病的相关性研究

目的:研究中国华南地区汉族人脂联素基因SNP+45T/G单核苷酸多态性与冠心病的相关性。方法:以153例冠脉造影证实为冠心病的非糖尿病患者为冠心病组,以73例健康者为对照组,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法分析脂联素基因SNP+45T/G单核苷酸多态性与冠心病的相关性,ELISA法测定血浆脂联素水平。结果:冠心病组T/G+G/G型频率、G等位基因频率均高于对照组(P0.05)。Logistic回归分析发现脂联素基因SNP+45 T/G+G/G型与冠心病正相关(OR:2.132,95.0%C I:1.034-4.397,P0.05),血浆脂联素水平与冠心病的发病呈负相关(OR:0.868,95.0%C I:0.785-0.959,P0.05)。结论:脂联素基因SNP+45 T/G+G/G型可能是华南地区汉族人冠心病的易感基因型。     

Angiotensin-I-converting enzyme (ACE) insertion/deletion polymorphism in Mexican patients with coronary artery disease. Association with the disease but not with lipid levels

Angiotensin-I-converting enzyme (ACE) insertion/deletion (ID) polymorphism has been associated with the genetic susceptibility to coronary artery disease (CAD) and also with the lipid profile in several populations. In the present work, we analyzed the distribution of ID polymorphism in 147 Mexican patients with CAD and 100 unrelated healthy controls. The correlation of this polymorphism with the lipid profile (cholesterol, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, high density lipoprotein-cholesterol and triglycerides) in the patients group was determined. Increased frequency of D allele as well as DD genotype and decreased frequency of I allele and II genotype were found in CAD patients group (pC = 0.00058, OR = 1.96, pC = 0.021, OR = 2.5 and pC = 0.00058, OR = 0.51, pC = 0.0028, OR = 0.38). Correlation between ID genotypes and lipid profile in patients was carried out in total population and separately for females and males. After they had been adjusted for age, sex and BMI, there was no association among the three genotypes (II, ID and DD) and lipids and lipoproteins in none of the studied groups. Our data suggest that genetic variation at the ACE is a genetic factor related with the susceptibility to coronary artery disease in the Mexican Mestizo population.     

High prevalence of peripheral arterial disease in Korean patients with coronary or cerebrovascular disease

This prospective study surveyed the prevalence of peripheral arterial disease (PAD) in Korean patients with coronary arterial disease (CAD) or cerebrovascular disorder (CVD). From March 2010, 576 hospitalized patients in cardiovascular or stroke center were enrolled as the study group. Ankle-brachial index (ABI) was measured and the cut-off point for diagnosing PAD was ≤ 0.9 at rest. A total of 424 hospitalized patients in the Department of Surgery and aged ≥ 50 yr was enrolled as the control group. The prevalence of PAD was significantly higher in the study group than the control group (7.6% vs 1.7%; P < 0.001). To analyze the relationship of other vascular diseases and PAD, the patients were regrouped; group A (no CAD or CVD), group B (CAD only), group C (CVD only), and group D (CAD and CVD). Compared with group A, those with other vascular diseases (group B, C, D) had significantly higher prevalence of PAD, diabetes, dyslipidemia, renal insufficiency and claudication. The trend that patients with CAD or CVD are at risk of PAD is observed in this cross-sectional study in Koreans. Routine ABI measurement is recommended in these high-risk groups for early detection and proper management of PAD.