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PubMed1994

Genetic polymorphism for glutathione-S-transferase mu in asbestos cement workers.

OBJECTIVE: To investigate whether a lack of glutathione-S-transferase mu (GSTM1) activity was related to an increased risk for adverse outcome after asbestos exposure. METHODS: A study was made of 78 male former asbestos cement workers, with retrospective cohort data on exposure, radiographical findings, and lung function. Venous blood samples were obtained for the analysis of GSTM1 polymorphism by the polymerase chain reaction technique. Chest x ray films were classified according to the International Labour Organisation (ILO) 1980 classification. Vital capacity (VC) and forced expiratory volume during 1 s (FEV1) were determined. Individual estimates of asbestos exposure were calculated, and expressed as duration of exposure, average exposure intensity, and cumulative dose. Data on smoking were obtained from interviews. RESULTS: The lung function in the study group was reduced, compared with reference equations. 23% of the workers had small opacities > or = 1/0, 29% circumscribed pleural thickenings, 14% diffuse thickenings, and 12% obliterated costophrenic angles. 54% of the workers were GSTM1 deficient. They were comparable with the other workers in age, follow up time (median 30 years), and duration of exposure (median 18 years), but had a slightly higher cumulated dose (median 18 v 10 fibre-years) than the others. Neither in radiographical changes nor lung function variables were there any differences between the different GSTM1 groups. The findings were similar when smoking habits and estimated asbestos exposure were taken into account. CONCLUSIONS: We could not show that lack of GSTM1 activity was related to an increased risk for radiographical or lung function changes in a group of asbestos cement workers, followed up for a long period after the end of exposure.

Aged↗
PubMed1985

Genetic polymorphism in populations of Akodon rodents.

By means of starch gel electrophoresis, 16-20 loci coding for enzymes and hemoglobin have been investigated in six population samples of Akodon dolores, captured in a single site of the Córdoba province (Argentina) during a 3-year period and in three samples of an Akodon azarae population. Proportion of polymorphic loci (P) ranged from 0.278 to 0.389 in A. dolores and from 0.166 to 0.300 in A. azarae. Mean heterozygosity (H) ranged from 0.138 to 0.192 in A. dolores and from 0.099 to 0.118 in A. azarae. These values are very high compared with those reported for northern hemisphere rodent populations. The high value is remarkable since the loci sample is biased towards the less variable (group I) enzymes.

Animals↗
PubMed2002

Genetic polymorphisms of the human MDR1 drug transporter.

P-glycoprotein is an ATP-dependent efflux pump that contributes to the protection of the body from environmental toxins. It transports a huge variety of structurally diverse compounds. P-glycoprotein is involved in limiting absorption of xenobiotics from the gut lumen, in protection of sensitive tissues (brain, fetus, testis), and in biliary and urinary excretion of its substrates. P-glycoprotein can be inhibited or induced by xenobiotics, thereby contributing to variable drug disposition and drug interactions. Recently, several SNPs have been identified in the MDR1 gene, some of which can affect P-glycoprotein expression and function. Potential implications of MDR1 polymorphisms for drug disposition, drug effects, and disease risk are discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Selected genetic polymorphisms and plasma coagulation factor VII changes with exercise training.

We assessed the effects of coagulation factor VII (FVII) gene polymorphisms, lipid-related polymorphisms, and exercise training-induced plasma lipoprotein lipid changes on FVII level changes with exercise training in middle- to older-aged men and women. Forty-six healthy sedentary men and women were stabilized on a low-fat diet and then underwent baseline testing, 6 mo of endurance exercise training, and final testing. Plasma FVII-Ag levels decreased with exercise training (106.7 +/- 1.4 vs. 104.2 +/- 1.6%, P = 0.005). There were no significant differences in FVII-Ag changes with exercise training between -323 (0/10 bp)/-401 (G/T) haplotype or -402 (G/A) genotype groups. FVII-Ag changes with training were not correlated with changes in plasma lipoprotein lipids. In linear regression analyses, FVII-Ag changes with training remained significant after adjusting for training-induced plasma lipoprotein lipid changes (P = 0.01). FVII changes with training were associated with apolipoprotein E genotype (P = 0.012); this relationship was still evident after adjusting for training-induced plasma lipoprotein lipid changes (P = 0.047). FVII changes with training also were significantly associated with human ATPase binding cassette-1 genotype (P = 0.018); this relationship persisted after accounting for the effect of the training-induced plasma lipoprotein lipid changes (P = 0.045). We conclude that plasma FVII-Ag changes with exercise training are more closely related to selected lipid-related genotypes than FVII gene promoter variants.

Aged↗
PubMed2005

CYP1A1 genetic polymorphisms in Ecuador, South America.

A total of 108 individuals from the Ecuadorian population from rural and urban places were analyzed for two CYP1A1 gene polymorphisms. The frequency of the val allele at codon 462 was 0.50, while the frequency of the Msp I restriction site, m2 allele at the T6235C position was 0.70. These polymorphisms in Ecuador have higher frequencies if we compare with others around the world, with the exception of some South American population in Brazil and Chile.

Adult↗
PubMed2005

[Arterial thrombosis and genetic polymorphisms: too many actors, complex scenario].

Arterial thrombosis results from complex gene-gene and gene-environment interactions. While Vichow's triad was traditionally referred to venous thrombosis, the same process has been applied to arterial thrombosis: abnormalities of hemorrheology, abnormal blood constituents and abnormal vessel wall/endothelial dysfunction. Research carried out in the past decade has identified several polymorphisms in genes related to coagulation and fibrinolytic factors, platelet receptors, endothelial dysfunction, homocysteine metabolism, endothelial nitric oxide synthase, abnormal blood flow and oxidative stress. Whereas the individual contribution of each polymorphism to the overall cardiovascular risk seems to be modest, multiple gene-gene and gene-environment interactions appear more relevant in the pathogenesis of arterial thrombosis.

Blood Coagulation Factors↗
PubMed2006

Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol-induced cirrhosis.

Manganese superoxide dismutase (MnSOD) converts the superoxide anion into H(2)O(2), which, unless it is detoxified by glutathione peroxidase 1 (GPx1), can increase hepatic iron and can react with iron to form genotoxic compounds. We investigated the role of Ala/Val-MnSOD and Pro/Leu-GPx1 polymorphisms on hepatic iron accumulation and hepatocellular carcinoma development in patients with alcoholic cirrhosis. Genotypes were determined in 162 alcoholic patients with cirrhosis but without hepatocellular carcinoma initially, who were prospectively followed up for hepatocellular carcinoma development. We found that patients with two Val-MnSOD alleles (slow H(2)O(2) production) and two Pro-GPx1 alleles (presumably quick H(2)O(2) detoxification) had a lower risk of hepatocellular carcinoma development than other patients (chi(2) trend test, P = 0.001; log-rank, P = 0.0009). Indeed, hepatocellular carcinoma percentage was 0% in subjects with this "2Val-MnSOD/2Pro-GPx1" genotype versus 16%, 27%, and 32% in "2Val-MnSOD/1or2Leu-GPx1," "1or2Ala-MnSOD/2Pro-GPx1," and "1or2Ala-MnSOD/1or2Leu-GPx1" patients, respectively. The percentage of patients with stainable hepatic iron increased progressively with these genotypic associations: 22%, 28%, 50%, and 53%, respectively (chi(2) trend test, P = 0.005). Stainable iron was a risk factor for hepatocellular carcinoma (log-rank, P = 0.0002; relative risk, 3.40). In conclusion, polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in French alcoholic patients with cirrhosis.

Alleles↗
PubMed2005

Association of genetic polymorphisms with serum estrogens measured multiple times during a 2-year period in premenopausal women.

There is evidence that circulating estrogens are associated with breast cancer risk. In this study of premenopausal women, we explored the association of polymorphisms in genes in the estrogen synthesis and metabolism pathways with serum and urinary levels of estrone (E1) and estradiol (E2) and with the urinary ratio of 2-hydroxyestrone (2-OHE1)/16alpha-hydroxyestrone (16alpha-OHE1). This analysis included 220 women, who were participants in a 2-year randomized soy intervention. Blood specimens were collected in the luteal phase of the menstrual cycle an average of 4.4 times over 2 years. Overnight urinary specimens were collected on the same cycle day, only at baseline. Levels of E1, E2, 2-OHE1, and 16alpha-OHE1 were measured by enzyme immunoassays. The DNA samples were analyzed by PCR/RFLP for the COMT Val158Met, CYP1A1*2A, CYP1A1*2B, CYP1A2*1F, CYP1B1 Val432Leu, and CYP17 T27C polymorphisms. We applied mixed models to investigate the relations between genotypes and repeated serum hormone measurements and generalized linear models to assess associations between genotypes and urinary estrogen metabolites. The CYP1A2 C allele was significantly associated with lower serum E2 levels; in CC genotype carriers, serum E2 levels were 26.3% lower than in homo- and heterozygous common allele carriers combined (P = 0.01). CYP1A2*1F also affected the urinary 2-OHE1/16alpha-OHE1 ratio; carriers of the variant C allele had a markedly lower ratio than individuals with the AA genotype (1.37 versus 1.76; P = 0.002). These data suggest that CYP1A2*1F is associated with lower circulating levels of E2, and that it may be a susceptibility locus for breast cancer.

Adult↗
PubMed2005

Genetic polymorphisms of the transforming growth factor-beta1 gene and breast cancer risk: a possible dual role at different cancer stages.

Transforming growth factor-beta (TGF-beta) inhibits the proliferation of carcinomas in early stages of breast cancer, whereas it promotes tumor growth and metastasis in later stages of cancer. We evaluated a possible association between TGF-beta1 gene polymorphisms and breast cancer risk in a population-based case-control study of Chinese women living in Shanghai, which included 1,127 breast cancer cases and 1,228 population controls. Two polymorphisms, C-509T and T+29C, were in strong linkage disequilibrium. There were no overall differences in the genotype distribution of T+29C polymorphisms of the TGF-beta1 gene among cases and controls. However, the distribution of the high-activity C allele of T+29C polymorphisms differed by cancer stages (P(trend) = 0.02). This allele was associated with decreased risk of early-stage breast cancer [stages 0 and I; odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54-0.99], and the OR was further reduced to 0.66 (95% CI, 0.45-0.96) for those homozygous for this allele (P(trend) = 0.03). On the other hand, the same allele was associated with nonsignificantly increased risk of breast cancer with advanced stages III and IV (OR, 1.33; 95% CI, 0.81-2.18), which differed significantly from that observed for early-stage cancer (P = 0.04). This result suggests a possible dual effect of TGF-beta1 shown by in vitro experiments and provides an explanation for some of the inconsistent findings from previous epidemiologic studies that did not evaluate this association by cancer stage.

Adult↗
PubMed2005

Estrogen bioactivation, genetic polymorphisms, and ovarian cancer.

Recent experimental evidence has shown that catechol estrogens can be activated through metabolism to form depurinating DNA adducts and thereby initiate cancer. Limited data are available regarding this pathway in epithelial ovarian cancer. We conducted a case-control study of 503 incident epithelial ovarian cancer cases at the Mayo Clinic in Rochester, MN, and Jacksonville, FL, and a 48-county region in North Carolina. Six hundred nine cancer-free controls were frequency matched to the cases on age, race, and residence. After an interview to obtain data on risk factors, a sample of blood was collected for DNA isolation. Subjects were genotyped for seven common single nucleotide polymorphisms in four genes involved in catechol estrogen formation (CYP1A1 and CYP1B1) or conjugation (COMT and SULT1A1). Data were analyzed using logistic regression, stratified by race, and with adjustment for design factors and potential confounders. None of the individual genotypes were significantly associated with ovarian cancer risk. However, an oligogenic model that considered the joint effects of the four candidate genes provided evidence for an association between combinations of these genes and ovarian cancer status (P = 0.015). Although preliminary, this study provides some support for the hypothesis that low-penetrance susceptibility alleles may influence risk of epithelial ovarian cancer.

Adult↗
PubMed2005

Genetic polymorphisms of flavin monooxygenase 3 in sulindac-induced regression of colorectal adenomas in familial adenomatous polyposis.

Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance-M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.

Adenoma↗
PubMed2006

Dietary selenium intake and genetic polymorphisms of the GSTP1 and p53 genes on the risk of esophageal squamous cell carcinoma.

Few studies have assessed potential effect modifications by polymorphisms of susceptibility genes on the association between selenium intake and esophageal squamous cell carcinoma (ESCC). We studied the joint effects of dietary selenium and the GSTP1 and p53 polymorphisms on ESCC risk in a population-based case-control study with 218 ESCC cases and 415 controls in Taixing City, China. Dietary selenium intake was estimated from a food frequency questionnaire with 97 food items. GSTP1 and p53 polymorphisms were detected by RFLP-PCR assays. Logistic regression analyses were done to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Reduced ESCC risk was observed among individuals in the highest quartile of dietary selenium intake (adjusted OR, 0.31; 95% CI, 0.13-0.70) with a dose-dependent gradient (P(trend) = 0.01). The p53 Pro/Pro genotype was associated with increased risk of ESCC compared with the Arg/Arg genotype (adjusted OR, 2.02; 95% CI, 1.19-3.42). When combined with selenium consumption, an obvious increased risk was observed among individuals with the p53 Pro/Pro or GSTP1 Ile/Ile genotype with adjusted ORs of 3.19 (95% CI, 1.74-5.84) and 1.90 (95% CI, 1.03-3.51), respectively. Among smokers and alcohol drinkers, elevation of ESCC risk was more prominent among p53 Pro/Pro individuals who consumed a low level of dietary selenium (adjusted OR, 3.59; 95% CI, 1.49-8.66 for smokers and 6.19; 95% CI, 1.83-20.9 for drinkers). Our study suggests that the effect of dietary selenium on the risk of ESCC may be modulated by tobacco smoking, alcohol drinking, and p53 Pro/Pro and GSTP1 Ile/Ile genotypes.

Aged↗
PubMed2006

Prostate cancer risk in relation to selected genetic polymorphisms in insulin-like growth factor-I, insulin-like growth factor binding protein-3, and insulin-like growth factor-I receptor.

We conducted a nested case-control study within a cohort of elderly Americans to examine the role of the insulin-like growth factor (IGF) signaling pathway in prostate cancer etiology. The distribution of genotypes of IGF-I (CA)n, IGF binding protein-3 (IGFBP-3) A-202C, and of the 2-bp deletion and (AGG)n polymorphisms in IGF-I receptor (IGF-IR) was compared between men with prostate cancer (n = 213) and equal number of controls matched on year of blood draw, survival until the date of diagnosis, race, and age. Among controls, the number of CA repeats in IGF-I was not correlated to any appreciable degree with plasma IGF-I concentration, whereas the IGFBP-3 CC genotype was associated with a relatively low level of plasma IGFBP-3. There was no association between prostate cancer risk and the number of CA repeats in IGF-I, IGFBP-3 genotype, or the presence of the 2-bp deletion in IGF-IR. There was a small increased risk among men who did not carry two copies of the (AGG)7 allele of IGF-IR. These results add to the evidence that the number of IGF-I CA repeats is not associated with prostate cancer risk. Our observation that men who do not carry two copies of the IGF-IR (AGG)7 allele are at increased risk of prostate cancer merits further investigation.

Aged↗
PubMed2004

Genetic polymorphisms of human flavin monooxygenase 3 in sulindac-mediated primary chemoprevention of familial adenomatous polyposis.

PURPOSE: Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) effective in regressing adenomas in patients with familial adenomatous polyposis (FAP). However, a recent randomized trial showed that sulindac, when compared with placebo, failed to prevent the development of adenomatous polyps in genotypically positive but phenotypically negative FAP patients. The present study determined whether polymorphisms in the gene encoding flavin monooxygenase 3 (FMO3), a hepatic microsomal enzyme that inactivates sulindac, played a role in determining the efficacy of sulindac in preventing polyposis in this cohort of FAP patients. EXPERIMENTAL DESIGN: Genotyping was performed on seven established FMO3 polymorphisms previously shown to have functional relevance-M66I, P153L, E158K, V257M, E305X, E308G, and R492W-in 21 and 20 FAP patients, who received sulindac and placebo, respectively. RESULTS: None of the 41 patients exhibited heterozygous or homozygous M66I and R492W variant alleles, or homozygous P153L, V257M, and E305X variant alleles. Among sulindac-treated patients who did not develop adenomas ("responders"), 4 (33%) were homozygous for E158K and 2 (17%) were homozygous for E308G variant alleles. In contrast, none of the patients on sulindac who developed adenomas ("nonresponders") exhibited homozygosity for either of the two variant alleles. In addition, polymorphisms in the E158K or E308G allele were associated with a significant reduction in mucosal prostanoid levels in patients treated with sulindac. CONCLUSIONS: Polymorphisms in FMO3, particularly at the E158K and E308G loci, may reduce activity in catabolizing sulindac and result in an increased efficacy to prevent polyposis in FAP.

Adenomatous Polyposis Coli↗
PubMed2000

New perspectives in gastric acid suppression: genetic polymorphisms predict the efficacy of proton pump inhibitors.

Proton pump inhibitors are highly effective in the management of acid-peptic diseases. These drugs potently inhibit acid secretion from gastric parietal cells by irreversibly inhibiting activity of the H(+), K(+) ATPase (proton pump). Early studies of the pharmacokinetics of proton pump inhibitors demonstrated considerable variation in drug clearance rates among patients and healthy volunteers. This variation was also reflected in a wide range of the efficacy of acid suppression by standard doses of proton pump inhibitors among study subjects; those with slower clearance and higher drug concentrations experienced superior acid suppression. Proton pump inhibitors are predominantly inactivated by the 2C19 isoform of the hepatic cytochrome P450 mixed function oxidase system. The cytochrome P450 2C19 gene is polymorphic, with three known inactivating mutations. Individuals with one or two mutant cytochrome P450 2C19 alleles metabolize proton pump inhibitors more slowly than those with two wild-type alleles and experience higher drug levels. An individual's cytochrome P450 2C19 genotype predicts the degree of acid suppression in response to a standard dose of a proton pump inhibitor. Emerging data suggests that the clinical effectiveness of proton pump inhibitors in the treatment of acid-peptic diseases may also be dependent on cytochrome P450 2C19 genotype.

Cytochrome P-450 Enzyme System↗
PubMed1999

Genetic polymorphism of human complement factor I (C3b inactivator) in the Chinese Han population.

The human complement factor I (IF) polymorphism has been analysed by polyacrylamide gel isoelectric focusing electrophoresis of neuraminidase-treated EDTA plasma samples followed by immunoblotting and enzymatic detection. In a population study among 121 random individuals from Chengdu, PR China, three different common phenotypes were observed. The results show that IF is polymorphic in the Chinese population. The allele frequencies were as follows: FI*A = 0.153, FI*B = 0.847. The distribution of observed phenotypes was in accordance with the Hardy-Weinberg equilibrium. In comparison to other Asian population studies, the frequency of the IF*A allele was the highest in the Chinese population studied here.

Alleles↗