Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer studies suggest that the null polymorphisms of glutathione S-transferase M1 or T1 (GSTM1/GSTT1) may affect the ability to detoxify or activate chemicals in cigarette smoke. The potential modification of the association between smoking and coronary heart disease (CHD) by GSTM1 and GSTT1 has not been studied in humans. A case-cohort study was conducted to test the hypotheses that specific genotypes of GSTM1 or GSTT1 affect susceptibility to smoking-related CHD. CHD cases (n=400) accrued during 1987-1993 and a cohort-representative sample (n=924) were selected from a biracial cohort of 15792 middle-aged men and women in four US communities. A significantly higher frequency of GSTM1-0 and a lower frequency of GSTT1-0 were found in whites (GSTM1-0=47.1%, GSTT1-0=16.4%) than in African-Americans (AAs) (GSTM1-0=17.5%, GSTT1-0=25.9%). A smoking-GSTM1-0 interaction for the risk of CHD was statistically significant on an additive scale, with ever-smokers with GSTM1-0 at a approximately 1.5-fold higher risk relative to ever-smokers with GSTM1-1 and a approximately 2-fold higher risk relative to never-smokers with GSTM1-0, after adjustment for other CHD risk factors. The interaction between having smoked >/=20 pack-years and GSTT1-1 was statistically significant on both multiplicative and additive scales. The risk of CHD given both GSTT1-1 and >/=20 pack-years of smoking was approximately three times greater than the risk given exposure to >/=20 pack-years of smoking alone, and approximately four times greater than the risk given exposure to GSTT1-1 alone. The modification of the smoking-CHD association by GSTM1 or GSTT1 suggests that chemicals in cigarette smoke that are substrates for glutathione S-transferases may be involved in the etiology of CHD.
Atherosclerosis 2000 Apr
PMID:Glutathione S-transferase genotype as a susceptibility factor in smoking-related coronary heart disease. 1072 97

Glutathione S-transferases M1 or T1 (GSTM1/GSTT1) affect the body's ability either to detoxify or to activate chemicals in cigarette smoke. Cigarette smoking increases the risk of lower extremity arterial disease (LEAD). We conducted a cross-sectional study to evaluate a hypothesized interaction of the genetic polymorphisms of GSTM1 and T1 with cigarette smoking in the risk of LEAD in the ARIC study. A stratified-random sample, including 212 LEAD cases (ankle-brachial index <0.9 in men or <0.85 in women) and 1277 non-cases, was selected from the ARIC cohort of 12041 middle-aged participants free of CHD, transient ischemic attack and stroke at baseline (1987-1989). Overall, the differences in the frequencies of GSTM1-0 and GSTT1-0 (the homozygous deletion genotype) were not statistically significant between cases and non-cases (44 vs. 41% and 28 vs. 18%). However, smoking was more prevalent among LEAD cases than non-cases. The results suggest that the non-deletion genotype GSTM1-1 interacts with smoking to increase the risk of LEAD, but this interaction was not statistically significant. The functional genotype GSTT1-1 was significantly associated with increased risk of LEAD given smoking after adjustment for other risk factors. In individuals with GSTT1-1, the odds ratios (ORs) (95% confidence intervals) of LEAD were 3.6 (1.4, 9.0) for current smoking and 5.0 (1.9, 13.0) for 20+ pack-years. However, in those with GSTT1-0, the ORs were 0.8 (0.2, 2.8) for current smoking and 0.6 (0.1, 2.1) for 20+ pack-years. The interaction was significant (P<0.05) on the additive scale for current smoking and on both the additive and multiplicative scales for 20+ pack-years. Among non-smokers, GSTT1-1 was not associated with LEAD. The results suggest that the GSTT1-1 polymorphism may be a susceptibility factor modifying the risk of LEAD associated with cigarette smoking.
Atherosclerosis 2001 Feb 15
PMID:Interaction of the glutathione S-transferase genes and cigarette smoking on risk of lower extremity arterial disease: the Atherosclerosis Risk in Communities (ARIC) study. 1125 76

Reduced glutathione (GSH) plays a critical role as an intracellular defense system providing detoxification of a broad spectrum of reactive species and their excretion as water-soluble conjugates. Conjugation of GSH with electrophiles is catalyzed by GSH S-transferases (GST), which constitute a broad family of phase II isoenzymes. Two of the GST encoding genes, GSTM1 (mu) and GSTT1 (theta), have a null genotype due to their homozygous deletion that results in lack of active protein. Polymorphisms within GSTT1 and especially GSTM1 have often been associated with cancer in various organs as well as with elevated levels of DNA adducts in various cell types. We recently demonstrated that DNA adducts are consistently detectable in smooth muscle cells (SMC) of human abdominal aorta affected by atherosclerotic lesions. Here we provide evidence that levels of adducts to SMC DNA from atherosclerotic lesions are consistently increased in individuals having the null GSTM1 genotype, whereas no association was established with the GSTT1 polymorphism. The influence of GSTM1 deletion was better expressed in never-smokers and ex-smokers than in current smokers. These findings bear relevance to the epidemiology of atherosclerosis and suggest that metabolic polymorphisms may contribute to the interindividual variability in susceptibility not only to carcinogens, but also to DNA binding atherogens.
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PMID:Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype. 1125 93

We hypothesize that smokers with the null genotype for GSTM1 (GSTM1-0), who thus lack the detoxification enzyme glutathione S-transferase mu-1, develop atherosclerosis at an increased rate compared to smokers with the positive genotype (GSTM1-1). We used data from a 2-year randomized placebo-controlled trial on the effect of vitamin E on atherosclerosis among 189 male smokers. Progression of atherosclerosis was measured by 2-year change of the common carotid intima media thickness (CCA-IMT) as measured by B-mode ultrasonography. The frequency of GSTM1-0 genotype was 0.5 in both the placebo and the vitamin E group. Smokers with GSTM1-0 genotype had a tendency to higher baseline CCA-IMT values than those with GSTM1-1 (0.97 versus 0.92 mm, P=0.09). Within the placebo group, more CCA-IMT progression was found for smokers with the GSTM1-0 than for smokers with the GSTM1-1 genotype after adjustment for baseline IMT and major CVD risk factors (0.050 versus -0.002 mm, P=0.046). In the vitamin E group no effect of GSTM1 genotype on atherosclerosis progression was found. Overall, smokers with GSTM1-0 genotype had a higher mean 2-year progression compared to those with GSTM1-1 as shown by a difference in increase of 0.042 mm (95% CI 0.006; 0.078, P=0.02). In conclusion, our data suggest that smokers lacking the detoxifying enzyme GST mu-1 develop progression of atherosclerosis at an increased rate.
Atherosclerosis 2001 Sep
PMID:Effect of glutathione S-transferase M1 genotype on progression of atherosclerosis in lifelong male smokers. 1150 Jan 95

Atherosclerosis and carcinogenesis may share some common mechanisms of the genotoxic action of exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs). The main objective of this study was to test the hypothesis that "bulky" aromatic DNA-adducts in smooth muscle cells (SMCs) of thoracic aortas taken at autopsy from sudden and accidental death male subjects, aged between 30 and 60 years (N=133), are associated with the stage of atherosclerosis. The subjects with severe atherosclerotic damage were treated as "Cases" (N=66). The subjects meeting diagnostic criteria for slight and moderate total atherosclerotic body damage were treated as "Controls" (N=67). An additional objective of the study was to evaluate the effect of known atherogenic risk factors and possible modifiers of atherosclerotic changes, such as age, smoking, plasma lipid and antioxidant vitamin levels and some genetic susceptibility markers, e.g. polymorphisms of GSTM1, GSTT1, NAT2, CYP1A1 or apolipoprotein E (APO E) genes. We found significantly higher DNA-adduct levels in "Cases" as compared with "Controls" (2.11+/-1.07 adducts/10(8) nucleotides versus 1.49+/-0.55 adducts/10(8) nucleotides, P<0.001). "Cases" were significantly older and had elevated heart weight and plasma cholesterol levels and a higher frequency of overweight subjects as compared with "Controls". No significant differences in DNA-adduct levels between smokers and non-smokers within either group were detected. Multivariate logistic regression revealed that the "bulky" aromatic DNA-adducts, which are the most likely related to environmental exposure to genotoxic chemicals, remain a statistically significant predictor of the stage of atherosclerosis (OR=3.76, 95% CI=1.54-9.18, P=0.004) even after adjustment for age, smoking, obesity, heart weight and genetic susceptibility markers (GSTT1 and CYP1A1-MspI polymorphisms) that were also significant predictors. The fact that the "bulky" aromatic DNA-adduct levels predict the progression of atherosclerosis independently of smoking indicates that the formation of atherosclerotic plaques may also be initiated by environmental exposures other than tobacco smoke.
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PMID:DNA-adducts and atherosclerosis: a study of accidental and sudden death males in the Czech Republic. 1193 43

Atherosclerosis (AR) is the leading cause of morbidity and mortality in the US and cigarette smoking is a major contributing factor to the disease. Like cigarette smoking in lung cancer, genetic susceptibility may be an important factor in determining who is more likely to develop AR. However, the current emphasis has been on susceptibility based on altered cardiovascular homeostasis. In this investigation, we studied 120 AR patients and 90 matched controls to elucidate the association between polymorphisms in some metabolizing genes (GSTM1, GSTT1, CYP2E1, mEH, PON1, and MPO) and susceptibility to AR. We found that the GSTT1 null allele and the fast allele of mEH(*) (exon 4) are associated with risk for AR. Furthermore, the combined genotypes GSTM1 null/ CYP2E1(*)5B, GSTM1 null/mEH YY, and GSTT1 null/mEH YY are significantly associated with susceptibility to AR (OR = 15.42, 95% CI = 1.33-77.93, P = 0.021; OR = 3.48, 95% CI = 1.63-8.04, P = 0.0008; OR = 3.4; 95% CI = 0.99-17.38, P = 0.05; respectively). We have also conducted cytogenetic analysis to elucidate if induction of chromosome aberrations (CAs) is a biomarker of AR susceptibility. We found that among cigarette smokers (AR patients and smoker controls), individuals having the GSTM1 null allele had a significantly higher frequency of CAs compared to those with the normal allele (P < 0.05). This association was not found among nonsmokers. In addition, individuals who had inherited the CYP2E1(*)5B allele exhibited a significantly higher CA frequency (8.0 +/- 0.82) compared to those with the CYP2E1 wild-type genotype (4.31 +/- 0.35). Since the analysis of genetic susceptibility factors is still in its infancy, our study may stimulate additional investigations to understand the roles of genetic susceptibility and cigarette smoking in AR.
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PMID:Polymorphic metabolizing genes and susceptibility to atherosclerosis among cigarette smokers. 1235 48

We assessed the contribution of genetic polymorphisms of glutathione S-transferase M1 ( GSTM1), T1 ( GSTT1), and P1 ( GSTP1, Ile105Val) to carotid atherosclerosis in 40 postmenopausal rheumatoid arthritic (RA) women without histories of smoking. We measured mean intima-media thickness (IMT) and plaque of the common carotid arteries by ultrasonography and evaluated relationships among the known risk factors for atherosclerosis, genetic polymorphisms, RA outcomes, and markers of inflammation. Subjects with the GSTT1-0 genotype had greater IMT ( P<0.05). On univariate analysis, carotid IMT was positively associated with age, systolic BP, antihypertensive drug use, and the GSTT1-0 genotype ( P<0.05). When compared to subjects with a double-positive GSTM1/T1 genotype, IMT in those with concurrent lack of the GSTM1 and GSTT1 genes was significantly increased ( P=0.008). This study suggests that the GSTT1-0 genotype might have an interaction with carotid atherosclerosis related to RA in Korean postmenopausal RA women without histories of smoking.
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PMID:Glutathione S-transferase M1, T1, and P1 gene polymorphisms and carotid atherosclerosis in Korean patients with rheumatoid arthritis. 1287 72

Recent epidemiologic studies suggest that polymorphisms of glutathione-S-transferases M1 and T1 (GSTM1/GSTT1) modify the effects of cigarette smoking on risk of coronary heart disease (CHD). Since GSTs are able to detoxify numerous toxic compounds and products of oxidative stress, it is possible that GST genotypes may also modify the capacity of smoking to invoke a chronic inflammatory response. A cross-sectional analysis, using a subset of participants (n = 989) in a large (n = 15, 792) biracial cohort, was used to evaluate levels of nine markers of inflammation, hemostasis, and endothelial function by different combinations of GST genotypes and cigarette smoking status. Participants with the GSTM1 null (GSTM1-0) genotype and > or = 20 pack-years of smoking had the highest mean levels of CRP, fibrinogen, von Willebrand factor, ICAM-1, and VCAM-1 and lowest mean levels of albumin compared to other combinations of genotype and smoking. However, a formal test for interaction between GSTM1 genotype and smoking was statistically significant only for albumin. By contrast, participants who had the functional GSTT1 genotype (GSTT1-1) and smoked > or = 20 pack-years had the highest mean levels of only CRP and fibrinogen. The results of this study provide some limited evidence that GSTM1 and GSTT1 polymorphisms modify the effect of smoking on inflammation, hemostasis, and endothelial function.
Atherosclerosis 2003 Dec
PMID:Glutathione-S-transferase genotypes, smoking, and their association with markers of inflammation, hemostasis, and endothelial function: the atherosclerosis risk in communities (ARIC) study. 1464 96

There is little doubt that cigarette smoking remains a major environmental health risk that humans are facing in the twenty-first century. Cigarette smokers are more likely to develop many forms of diseases than nonsmokers, including cancers and vascular diseases. With the availability of the human genome sequence, we become more aware of the genetic contributions to these common diseases, especially the interactive relations between environmental factors (e.g., smoking) and genes on disease susceptibility, development, and prognosis. Although smoking is responsible for up to 30% of pancreatic cancers and about 10% of cases are ascribed to genetic reasons, some genetic variants do not predispose carriers to disease development unless they are exposed to a specific adverse environment such as smoking. This smoke-gene interaction could potentially be responsible for most of the cases. Certain polymorphisms in genes such as CYP1A1 have been shown particularly sensitive to smoking-induced pathogenesis, including pancreatic cancer and atherosclerosis. We found that individuals with CYP1A1 CC genotype had a more than three fold increase in risk for severe coronary atherosclerosis when they smoked. Patients with endothelial nitric oxide synthase (eNOS) intron 4 27 repeat homozygotes were more likely to develop severe coronary stenosis when they smoked. On the other hand, DNA variants at the eNOS gene also dictate how smoking affects the expression of eNOS. We showed that GSTM1 deficiency was not involved in smoking-induced vascular diseases, but p53 polymorphisms tended to modify the disease severity in smokers. We are still at an early stage of defining the pairs and mechanisms of smoke-gene interaction, and this etiologic mechanism may hold great potential for risk assessment, treatment strategy, and prognostic predictions.
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PMID:Smoking-gene interaction and disease development: relevance to pancreatic cancer and atherosclerosis. 1569 95

A prospective molecular epidemiology study was implemented in a cohort of 98 subjects suffering from severe atherosclerotic lesions requiring removal of an abdominal aorta fragment. We previously published the results relative to detection, in the aorta medium layer, of bulky DNA adducts and fluorescent polycyclic aromatic hydrocarbon-related DNA adducts, oxidative DNA damage, and mitochondrial DNA 4977 common deletion, as well as GSTM1 and GSTT1 gene polymorphisms. We report herein new data, relative to oxidative stress biomarkers, including oxidative DNA damage in both inner and medium aorta layers, malondialdehyde in the medium layer, homocysteine and reduced glutathione in plasma, and those relative to additional gene polymorphisms, including NAT1, NAT2, OGG1, MTHFR, Leiden factor V, and prothrombin. The results of biochemical and molecular analyses were related to survival of the patients, whose average age was 70 at the start of the follow up. During the following 14 years, 71.4% of them died. The results obtained provide evidence for the crucial impact of oxidative stress and certain gene polymorphisms on clinical and biochemical patterns as well as on survival of patients. Survival was significantly affected not only by traditional risk factors for atherosclerosis but also by molecular end-points and adverse gene polymorphisms, and by their combinations.
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PMID:Survival of atherosclerotic patients as related to oxidative stress and gene polymorphisms. 1738 90


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