Metabolic Genetic Polymorphisms Research Articles

Folate Metabolism Genetic Polymorphisms and the Susceptibility to Parkinson Disease

Folate Metabolism Genetic Polymorphisms and the Susceptibility to Parkinson Disease

Association Between MTHFR Genetic Polymorphism and Parkinson's Disease Susceptibility: A Meta-analysis.

Folate metabolism plays quite a critical role in Parkinson’s disease (PD). Previous published research works have studied the link existing between the folate metabolism genetic polymorphisms and PD susceptibility; nevertheless, the results continue having controversies and inconclusiveness. Accordingly, we carried out the present meta-analysis for the assessment of the potential link between the folate metabolism genetic polymorphisms and the susceptibility to PD. In addition we carried out a literature search in the PubMed, EMBASE, Cochrane Library, and WanFang databases till November 10, 2018. The odds ratios (ORs) with corresponding 95% credible interval (95%CI) were put to use for evaluating the strength of the association of three folate metabolism genetic polymorphism ( C677T, A1298C, and A2756G) with the susceptibility to PD. Each statistical analysis was carried out with the use of STATA 15.0. An aggregate of twenty-one case-control investigations were retrieved, which involved 3,944 PD patients and 4,412 controls. We discovered the existence of no substantial link between the C677T and A1298C polymorphism and PD risk in any genetic framework comparisons. With regard to A2756G polymorphism, we discovered that there was an association between the A2756G genetic polymorphism and an augmented threat of PD in the co-dominant genetic framework (GG vs. AA: OR=1.86, 95%CI=1.02-3.37, P=0.042) and the recessive genetic model (GG vs. GA+AA: OR=1.90, 95%CI=1.06-3.41, P=0.031). To summarize, our research work indicates that the A2756G polymorphism of the folate metabolism gene had an association with an augmented threat of PD. Also, A1298C polymorphisms is unlikely to significantly contribute towards the susceptibility to PD. Further large-scale case-control studies are still required.

Role of the human N-acetyltransferase 2 genetic polymorphism in metabolism and genotoxicity of 4, 4'-methylenedianiline.

4, 4'-Methylenedianiline (MDA) is used extensively as a curing agent in the production of elastomers and is classified as reasonably anticipated to be a human carcinogen based on sufficient evidence in animal experiments. Human N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyze the N-acetylation of aromatic amines and NAT2 is subjected to a common genetic polymorphism in human populations separating individuals into rapid, intermediate, and slow acetylator phenotypes. Although MDA is known to undergo N-acetylation to mono- and di-acetyl metabolites, very little is known regarding whether this metabolism is subject to the NAT2 genetic polymorphism. We investigated the N-acetylation of MDA by recombinant human NAT1, NAT2, genetic variants of NAT2, and cryoplateable human hepatocytes obtained from rapid, intermediate and slow acetylators. MDA N-acetylation was catalyzed by both recombinant human NAT1 and NAT2 exhibiting a fivefold higher affinity for human NAT2. N-acetylation of MDA was acetylator genotype dependent as evidenced via its N-acetylation by recombinant human NAT2 genetic variants or by cryoplateable human hepatocytes. MDA N-acetylation to the mono-acetyl or di-acetyl-MDA was highest in rapid, lower in intermediate, and lowest in slow acetylator human hepatocytes. MDA-induced DNA damage in the human hepatocytes was dose-dependent and also acetylator genotype dependent with highest levels of DNA damage in rapid, lower in intermediate, and lowest in slow acetylator human hepatocytes under the same MDA exposure level. In summary, the N-acetylation of MDA by recombinant human NAT2 and cryopreserved human hepatocytes support an important role for the NAT2 genetic polymorphism in modifying MDA metabolism and genotoxicity and potentially carcinogenic risk.

Folate metabolism genetic polymorphisms and meningioma and glioma susceptibility in adults.

Polymorphic variants of genes involved in folate metabolism are implicated in the susceptibility to meningioma and glioma, but the results from published articles are controversial and inconclusive. Therefore, we performed this meta-analysis including all studies available to evaluate the relationship between folate metabolism genetic polymorphisms and the susceptibility to meningioma and glioma in adults. We searched the literature in PubMed, EMBASE and Cochrane Central Library for relevant articles published up to August 2016. The odds ratios (ORs) and the corresponding 95% confidence intervals (95%Cls) were used to evaluate the associations of two folate metabolism genetic variants MTRR A66G (rs1801394) and MTHFR A1298C (rs1801131) with the risk of meningioma and glioma in adults. We found significant association of MTHFR A1298C (rs1801131) variant genotypes with increased incidence of meningioma and glioma in this study population (CA vs. AA: OR=1.22, P<0.001; CA+CC vs. AA: OR=1.18, P=0.002). Moreover, we found that MTRR A66G (rs1801394) variant genotypes was associated with increased risk of meningioma and glioma (G vs. A: OR=1.11, P=0.020; GG vs. AA+AG: OR=1.17, P=0.043; GG vs. AA: OR=1.22, P=0.023). In conclusion, our meta-analysis suggests that two folate metabolism genetic variants MTRR A66G (rs1801394) and MTHFR A1298C (rs1801131) contribute to genetic susceptibility to meningioma and glioma in adults.

Antiplatelet Agents in Cardiology: A Report on Aspirin, Clopidogrel, Prasugrel, and Ticagrelor.

Antiplatelet drugs are the cornerstone of therapy in many cardiovascular conditions. With the current success and increased use of transcatheter aortic valve implantation (TAVI), the use of antiplatelet therapy is considered part of the medical therapy for these patients. Clinicians caring for these patients need to have a thorough understanding of the pharmacology, pharmacokinetics, pharmacodynamic, and clinical efficacy and safety of commonly used antiplatelet therapy. While aspirin therapy is widely used, dual antiplatelet therapy with clopidogrel has become part of standard of care. Despite the extensive experience with clopidogrel, there are limitations such as drug interactions, metabolism genetic polymorphisms, and variability in the antiplatelet response. More predictable and more potent antiplatelet agents, prasugrel and ticagrelor, have demonstrated superior reductions in ischemic endpoints as part of dual antiplatelet therapy compared to clopidogrel, but at the cost of more major bleeding in patients with an acute coronary syndrome. Significant research needs to be conducted in the setting of TAVI to help define the optimal antiplatelet regimen.

Effects of green and black tea consumption on brain wave activities in healthy volunteers as measured by a simplified Electroencephalogram (EEG): A feasibility study

Objectives: Tea has been associated with many mental benefits, such as attention enhancement, clarity of mind, and relaxation. These psychosomatic states can be measured in terms of brain activity using an electroencephalogram (EEG). Brain activity can be assessed either during a state of passive activity or when performing attention tasks and it can provide useful information about the brain's state. This study investigated the effects of green and black consumption on brain activity as measured by a simplified EEG, during passive activity.Methods: Eight healthy volunteers participated in the study. The EEG measurements were performed using a two channel EEG brain mapping instrument - HeadCoach™. Fast Fourier transform algorithm and EEGLAB toolbox using the Matlab software were used for data processing and analysis.Results: Alpha, theta, and beta wave activities were all found to increase after 1 hour of green and black tea consumption, albeit, with very considerable inter-individual variations.Discussion: Our findings provide further evidence for the putative beneficial effects of tea. The highly significant increase in theta waves (P < 0.004) between 30 minutes and 1 hour post-consumption of green tea may be an indication of its putative role in cognitive function, specifically alertness and attention. There were considerable inter-individual variations in response to the two teas which may be due genetic polymorphisms in metabolism and/or influence of variety/blend, dose and content of the selected products whose chemistry and therefore efficacy will have been influenced by ‘from field to shelf practices’.

Folate metabolism genes, dietary folate and response to antidepressant medications in late‐life depression

The primary aims of this study were to (i) determine whether folate metabolism genetic polymorphisms predict age of onset and occurrence of late life depression; and (ii) determine whether folate metabolism genetic polymorphisms predict response to antidepressant medications in late-life depression. This study used the Conte Center for the Neuroscience of Depression and the Neurocognitive Outcomes of Depression in the Elderly Study database, which includes individuals aged ≥60. The folate nutrition assessment was determined by the Block Food Frequency Questionnaire. Genotype was evaluated for 15 single nucleotide polymorphisms from 10 folate metabolism genes. Logistic regression models were used to examine genetic polymorphisms and folate estimates with association with depression age of onset and remission status. There were 304 Caucasians in the database, 106 of these were not depressed and 198 had a diagnosis of depression. There were no significant differences between remitters and non-remitters in age, sex or estimated folate intakes. There were no folate estimates or folate metabolism gene single nucleotide polymorphisms that significantly predicted age of onset of depression or occurrence of depression. Methionine synthase reductase (MTRR) A66G (rs1801394) was significantly associated with remission status (p = 0.0077) such that those with the AA genotype were 3.2 times as likely as those with the GG genotype to be in remission (p = 0.0020). Methylenetetrahydrofolate reductase A1298C (rs1801131) achieved a borderline significance for association with remission status (p = 0.0313). The major finding from this study is that the MTRR A66G genotype predicts response to selective serotonin reuptake inhibitor antidepressants in late life depression.

Genetic polymorphisms in metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine

Heterocyclic amines (HCAs) are naturally produced during common cooking processes for meats and fish. HCAs are metabolized by various enzymes, including cytochromes P450, N-acetyl transferases, and sulfotransferases, and their bioactivated metabolites are considered to bind to DNA or protein to show carcinogenic effects. More than 20 HCAs have been identified, of which 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is classified as 'reasonably anticipated to be a human carcinogen' to develop cancers in breast, colon and prostate. The purpose of this study was to evaluate human exposure levels of PhIP and to understand the role of genetic polymorphisms of enzymes on PhIP metabolism. Urine samples were collected from subjects (n = 100) before 3-day meat-restricted diets. Subjects consumed grilled chicken, and their blood and urine were collected before and after the administration of the chickens to investigate genetic polymorphisms and PhIP levels. The mean PhIP levels were 4.22 ± 0.12, 0.61 ± 0.19 and 22.64 ± 1.00 pg ml(-1) in urine under normal conditions and before and after chicken administration, respectively. Among 21 Single-nucleotide polymorphisms (SNP) of CYP1A1, CYP1A2, NATs and UGTs investigated in this study, genotypic groups of CYP1A1/T6235C (MSP I) and CYP1A2/-2467delT showed significant differences in PhIP excretion (P < 0.05). These results suggest that genetic polymorphisms might affect PhIP metabolism, which could improve understanding of populations subject to PhIP-derived health risk.

Association between 11 genetic polymorphisms in folate-metabolising genes and head and neck cancer risk

Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G, MTHFD1 G1958A, CBS 844ins68, TC2 C776G and A67G, SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ⩾49years (P<0.001), male gender (P=0.03), tobacco habit (P<0.001), MTHFR 1298AC/CC (P=0.028), MTR 2756AG/GG (P=0.010) and RFC1 80AG/GG (P=0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 (P=0.005); age ⩾49years and MTR 2756 AG/GG (P=0.004) and RFC1 80AG/GG (P=0.006) genotypes; male gender and MTHFR 1298 AC/CC (P=0.030), MTR 2756 AG/GG (P=0.006) and RFC1 80 AG/GG (P=0.009); tobacco non-habit and MTHFD1 1958GA/AA (P=0.040); tobacco and MTHFR 1298 AC/CC (P=0.054) and MTR 2756 AG/GG (P=0.010); alcohol non-consume and RFC1 80 AG/GG (P=0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours (P=0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

Abstract 5615: Global DNA methylation by LUMA predicts breast cancer risk in a population-based study

Abstract Global methylation dysregulation is a hallmark of cancer cells. Global methylation measurement in peripheral blood may be a predictor of cancer risk and prognosis. In this study, we used two independent assays, LUminometric Methylation Assay (LUMA) and LINE-1 methylation by pyrosequencing, to assess the global methylation content in the peripheral blood DNA from the Long Island Breast Cancer Study Project, a population-based case-control study. We examined the association between global methylation levels and: 1) the risk of developing breast cancer among 1055 cases and 1101 controls using logistic regression models; 2) the risk of mortality among breast cancer cases using Cox proportional hazards models; and 3) one-carbon metabolism genetic polymorphisms and dietary intake among controls using ANOVA. LUMA methylation levels were higher among cases (mean: 57.3%) than among controls (mean: 52.4%; p&amp;lt;0.001). Compared to women in the lowest quintile of LUMA methylation, those in the highest quintile had a 2.41-fold increase in the risk of developing breast cancer (95% CI: 1.83-3.16; p for trend &amp;lt; 0.0001). Risk was strongest for in situ breast cancer (OR: 6.18; 95% CI: 3.34-11.43), although the estimate is based on small numbers; but the association did not vary by other tumor characteristics, life-style or several established breast cancer risk factors. Among cases, there was an indication that high LUMA levels were associated with reduced breast cancer-specific mortality. Among controls, LUMA levels were associated with two SNPs in the one-carbon metabolism pathway, MTHFR C677T (p=0.001) and MTRR A66G (p=0.018), but not with dietary intake of one-carbon related nutrients. No association was observed between LINE-1 methylation and breast cancer risk, breast cancer-specific mortality, one-carbon metabolism SNPs or nutrients, or LUMA methylation. Our results suggest that LUMA methylation levels in peripheral blood DNA are associated with breast cancer development and progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5615. doi:10.1158/1538-7445.AM2011-5615

M13.6 One-carbon metabolism genetic polymorphisms in association with preeclampsia and small for gestational age babies

M13.6 One-carbon metabolism genetic polymorphisms in association with preeclampsia and small for gestational age babies

Glutathione S–Transferase M1 Polymorphism and Sporadic Colorectal Cancer Risk: An Updating Meta-Analysis and HuGE Review of 36 Case-Control Studies

Sporadic colorectal cancer (CRC) is considered to be a multifactorial disease, in which multiple exposures to endogenous factors interact with individual genetic background in a complex manner, resulting in modulation of the risk. The glutathione S-transferase M1 gene (GSTM1) is a particularly attractive candidate for CRC susceptibility because it codes an enzyme involved in the metabolism of environmental carcinogens. However, the epidemiological findings have been inconsistent. To evaluate this association, we performed an extensive meta-analysis of 36 case-control studies (including 10,009 cases and 15,070 controls). Overall, the combined data showed that GSTM1 deficiency is associated with a marginal effect on CRC risk (odds ratio [OR] = 1.13; 95% confidence interval [CI]: 1.03-1.23; P for heterogeneity <0.001). When stratified by race and tumor site, significant results were only observed in Caucasians (OR = 1.14, 95% CI: 1.01-1.27; P for heterogeneity <0.001), whereas no increased risk was detected in other subgroups. The findings of our study support the suggestion that GSTM1 polymorphism is associated with an increased risk of CRC, especially in the Caucasian population. Further investigation into the association between GSTM1 polymorphism and the risk of CRC is warranted and should include larger sample sizes and other genetic polymorphisms in metabolism of environmental carcinogens.

P57 Rheumatoid arthritis: phenomenology, personality profile, stress and their inter-relationship

Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G, MTHFD1 G1958A, CBS 844ins68, TC2 C776G and A67G, SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ⩾49 years (P < 0.001), male gender (P = 0.03), tobacco habit (P < 0.001), MTHFR 1298AC/CC (P = 0.028), MTR 2756AG/GG (P = 0.010) and RFC1 80AG/GG (P = 0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 (P = 0.005); age ⩾49 years and MTR 2756 AG/GG (P = 0.004) and RFC1 80AG/GG (P = 0.006) genotypes; male gender and MTHFR 1298 AC/CC (P = 0.030), MTR 2756 AG/GG (P = 0.006) and RFC1 80 AG/GG (P = 0.009); tobacco non-habit and MTHFD1 1958GA/AA (P = 0.040); tobacco and MTHFR 1298 AC/CC (P = 0.054) and MTR 2756 AG/GG (P = 0.010); alcohol non-consume and RFC1 80 AG/GG (P = 0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours (P = 0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

Finding a way through the forest: A Biopsychosocial model of hot flashes.

Finding a way through the forest: A Biopsychosocial model of hot flashes.

Candidate molecular markers associated with endocrine resistance in breast carcinoma

Genetic polymorphisms in folate metabolism may affect the risk of head and neck cancer (HNSCC) due to its involvement in DNA methylation and synthesis. We conducted a case-control study (265 HNSCC cases and 466 non-cancer controls) to investigate associations of MTHFR C677T and A1298C, MTR A2756G, MTRR A66G, RFC1 A80G, MTHFD1 G1958A, CBS 844ins68, TC2 C776G and A67G, SHMT C1420T and BHMT G742A polymorphisms with HNSCC risk. Interactions between polymorphisms and survival time, tobacco and alcohol habits, age, gender and tumour staging (TNM classification) were evaluated by multiple logistic regression analysis. We found that age ⩾49 years (P < 0.001), male gender (P = 0.03), tobacco habit (P < 0.001), MTHFR 1298AC/CC (P = 0.028), MTR 2756AG/GG (P = 0.010) and RFC1 80AG/GG (P = 0.015) genotypes were associated with an increased risk of HNSCC. There were interactions between lower survival and CBS 844ins68 (P = 0.005); age ⩾49 years and MTR 2756 AG/GG (P = 0.004) and RFC1 80AG/GG (P = 0.006) genotypes; male gender and MTHFR 1298 AC/CC (P = 0.030), MTR 2756 AG/GG (P = 0.006) and RFC1 80 AG/GG (P = 0.009); tobacco non-habit and MTHFD1 1958GA/AA (P = 0.040); tobacco and MTHFR 1298 AC/CC (P = 0.054) and MTR 2756 AG/GG (P = 0.010); alcohol non-consume and RFC1 80 AG/GG (P = 0.008) with HNSCC increased risk. MTHFR C677CT/TT genotypes were less frequently in advanced tumours (P = 0.04). In conclusion, our data provide evidence that folate metabolism genetic polymorphisms associated with variables as advanced age, male gender, tobacco and alcohol increase HNSCC development; CBS 844ins68 and MTHFR C677T polymorphisms are associated with less survival time and advanced stage tumours, respectively.

Fruit consumption reduces the effect of smoking on bladder cancer risk. The Belgian case control study on bladder cancer

We have hypothesized that consumption of fruit and vegetables may be associated with reduced risk of bladder cancer and that this may interact with cigarette smoking and metabolic genetic polymorphisms. A population-based case-control study was performed in the Belgian province of Limburg among 200 cases and 385 controls. Logistic regression was performed to calculate odds ratios (ORs) for bladder cancer occurrence with corresponding 95% confidence intervals (95% CI). Effect modification by smoking was investigated. We also evaluated interaction between fruit intake and GSTM1, GSTT1, NAT2 and SULT1A1 amongst "ever-smokers." Total vegetable intake was not significantly associated with the risk of bladder cancer (OR 1.15, 95% CI: 0.70-1.88 for the highest compared to the lowest tertile). However, total fruit intake was negatively associated with bladder cancer risk (OR 0.61, 95% CI 0.37-0.99 comparing the same tertiles). Among individuals with low daily fruit consumption, ever smokers had a highly increased risk of bladder cancer risk (OR: 4.23, 95% CI: 1.91-9.40). By increasing the daily fruit consumption, the risk of "ever-smokers" for developing bladder cancer decreased, however it remained significant (OR: 2.15; 95CI%: 1.15-4.05). No interaction was identified between the different genotypes and fruit consumption. We conclude that fruit consumption may decrease the effect of smoking on developing bladder cancer. Antioxidants, found in fruit, may protect against the damage caused by free radicals found in cigarette smoke. Metabolic polymorphisms appear not to modify this relation.

Does occupational exposure to PAHs, diesel and aromatic amines interact with smoking and metabolic genetic polymorphisms to increase the risk on bladder cancer?; The Belgian case control study on bladder cancer risk

To investigate the association between occupational exposure to polycyclic aromatic hydrocarbons, aromatic amines and diesel and bladder cancer risk and the modification by smoking and metabolic polymorphisms, have we recruited 200 cases and 385 population controls. The adjusted OR of bladder cancer was 5.75 (95%CI 2.09–15.83) comparing the highest tertile of the cumulative probability of occupational exposure to aromatic amines with no occupational exposure. A possible interaction between occupational exposures to aromatic amines and smoking was found. The increased ORs of GSTM1, GSTT1, NAT2 and SULT1A1 among those ever occupational exposed was explored by estimating the false–positive report probability. We confirm that occupational exposure to aromatic amines is associated with an increase in bladder cancer risk.

The role of genetic polymorphisms in metabolism of carcinogenic heterocyclic aromatic amines.

More than twenty heterocyclic aromatic amines (HAAs) have been identified in grilled meats, fish, poultry, and tobacco smoke condensate. HAAs are carcinogens and induce tumors at multiple sites in experimental laboratory animals. Because of the widespread occurrence of HAAs in foods, these chemicals may contribute to the etiology of several common human cancers that are associated with frequent consumption of grilled meats including colon, rectum, prostate, and breast. HAAs require metabolism in order to exert their genotoxic effects. Metabolic activation occurs by N-hydroxylation, a reaction catalyzed by cytochromes p450 (CYP). Some N-hydroxy-HAA metabolites may directly react with DNA, but further metabolism by N-acetyltransferases (NATs) or sulfotransferases (SULTs) may occur to form highly reactive N-acetoxy or N-sulfonyloxy esters that readily react with DNA bases. The N-acetoxy ester of the HAA 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is detoxified by glutathione S-transferases (GSTs), which catalyze the reduction of the reactive intermediate back to the parent amine. Some HAAs also undergo detoxification through conjugation reactions with the phase II enzymes such as UDP-glucuronosyltransferases (UGTs) or SULTs to form stable, polar products that are readily eliminated. All of these xenobiotic metabolism enzyme systems (XMEs) display common genetic polymorphisms, which may affect protein expression, protein stability, catalytic activity, and thus, the biological potency of these procarcinogens. In this review, the roles of common genetic polymorphisms of XMEs involved in HAA metabolism and cancer risk are discussed.

Risk assessment: the importance of genetic polymorphisms in man

Many genetic polymorphisms in metabolism enzymes are important for the risk of cancer as shown in a large number of case-control studies. The relative risk estimates have shown large variations between such population studies. However, in most studies the relative risk estimates are in the range of 2. Some polymorphisms are effect modifiers, i.e. without exposure they have no consequence and the effect of exposure can appear independent of the genotype. Genetic polymorphisms in metabolism of environmental toxicants plays a significant role in exposures to traffic generated air pollution in Copenhagen, revealing statistically significant higher levels of chromosomal aberrations in non-smoking bus drivers with glutathion- S-transferase M1, GSTM1 null and N-acetyltransferase 2, NAT2 slow genotypes. Combined with cohort studies showing positive associations between high chromosomal levels and increased cancer risk, such results indicate effect modification regarding cancer risk. In risk assessment the safety ‘factor’ of 10 is generally accepted to allow for variation in individual susceptibility. Reviewing the literature justifies the factor of 10 when considering single polymorphisms. However in an individual with several susceptible metabolism genotypes as well as other determinants of susceptibility, e.g. defective DNA repair, poor-nutritional state, etc. the risk may increase far above a safety of 10. Historically, genetic polymorphisms have been taken into consideration in employment and currently the application in insurance situations is criticised.

Functional characterization of nucleotide polymorphisms in the coding region of N-acetyltransferase 1.

N-acetyltransferase 1 (NAT1) catalyses the activation and/or deactivation of aromatic and heterocyclic amine carcinogens. A genetic polymorphism in NAT1 is associated with an increased risk of various cancers and drug toxicities, but epidemiological investigations are severely compromised by a poor understanding of the relationship between NAT1 genotype and phenotype. Human reference NAT1*4 and 12 known human NAT1 allelic variants possessing nucleotide polymorphisms in the NAT1 coding region were cloned and expressed in yeast (Schizosaccharomyces pombe). Large reductions in N- and O-acetyltransferase catalytic activities were observed for recombinant NAT1 allozymes encoded by NAT1*14B, NAT1*15, NAT1*17, NAT1*19 and NAT1*22. Each of these alleles exhibited NAT1 protein expression levels below the limit of detection as measured by Western blot. No differences between high and low activity NAT1 alleles were observed in relative mRNA expression or relative transformation efficiency. The recombinant NAT1 17 and NAT1 22 allozymes showed reduced intrinsic stability when compared with NAT1 4. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) N-acetylation was not catalysed by any of the NAT1 allozymes. Large differences in the metabolic activation via O-acetylation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP) were noted for NAT1 allelic variants. The results of these studies suggest an important role for the NAT1 genetic polymorphism in metabolism of aromatic and heterocyclic amine carcinogens. Furthermore, these results suggest that low NAT1 phenotype results from NAT1 allelic variants that encode reduced expression of NAT1 and/or less-stable NAT1 protein.