Each individual is represented by an open circle and the horizontal bars represent the mean in each group. Direct-Acting Antiviral Therapy in Liver Transplant Patients With Hepatocellular Carcinoma and Hepatitis C. Protocol for the development and validation of a risk prediction model for stillbirths from 35 weeks gestation in Australia. The association between coffee or caffeine intake and fetal death could be due to confounding or reverse causation. Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. We found that women with the combination of slow metabolizing genotypes had a tendency to drink more coffee and dependency may play a role for the daily consumption of caffeine,21 but studies on the association between genotypes and coffee consumption are few. Drugs metabolized by CYP2C19 and N-acetyltransferase 2 (NAT2) have been shown to exhibit difference s in metabolism due to genetic polymorphism. Compared with controls, the cases were older, were more often obese, and belonged to a lower socio-occupational group (Table 1). The information about outcome was then obtained from the women themselves. A polymorphism of the gene coding for CYP1A2, the enzyme responsible for 95% of caffeine metabolism, may potentially divide the population into ‘slow’ and ‘fast’ caffeine metabolisers 16,17. The genotypes were dichotomized for the analyses. Our aim was to determine whether genotypes related to caffeine metabolism and oxidative stress were associated with the risk of stillbirth. 2 It has been shown that NAT2 is polymorphic, and the lack of 2 functional alleles is responsible for decreased enzyme activity, conferring the slow acetylation phenotype. If caffeine has a biological effect on stillbirth, we would expect slow metabolizers of caffeine to have a higher risk of stillbirth at any given caffeine intake since the caffeine they consume will be eliminated less rapidly from the body. A total of 17 women experienced an intrapartum fetal death due to clinical causes, which we considered to be independent of the studied genotypes, and we, therefore, excluded intrapartum deaths from the primary analysis. .myheritage_ad_mobile ins { CYP1A2 genotype was grouped into fast oxidizers (A/A) and slow oxidizers (A/C and C/C). Results Slow oxidizer status (CYP1A2), slow acetylator status (NAT2), and low activity of GSTA1 were not individually associated with the risk of stillbirth [odds ratio (OR) = 1.06, 95% confidence interval (95% CI) 0.67â1.67, OR = 0.95, 95% CI 0.60â1.51, and OR = 1.42, 95% CI 0.88â2.28, respectively]. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Signorello LB, Nordmark A, Granath F et al. The alleles themselves are effectively haplotypes composed of several NAT2 SNPs, most typically assigned according to the status of the following seven SNPs: The most common alleles are then defined as follows: Almost all of the remaining common alleles are slow metabolizers, such as: However there are also a few rapid (i.e. Slow oxidizers and slow acetylators had a slightly higher risk of stillbirth (OR = 1.23, 95% CI 0.74â2.04), although this was not statistically significant. Tsutsumi K, Kotegawa T, Matsuki S et al. .myheritage_ad_mobile, Oxford University Press is a department of the University of Oxford. We then centrifuged the sample at 13â000 r.p.m. .myheritage_health_ad_container .myheritage_ad_desktop { NAT2 enzyme breaks down breaks down chemicals by adding the negatively charged acetyl chemical group, which causes the chemicals molecules to change shapes in ways that change their effects on the body. Background Cytochrome P4501A2 (CYP1A2) and N -acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. In slow acetylators, NAT2 levels are reduced. When only studying genotypes known to be active in caffeine metabolism, the present study does not support the hypothesis that caffeine in itself causes stillbirth, but we cannot rule out that other components in coffee may have this effect. .myheritage_ad_mobile img, An association between a combination of genotypes and stillbirth was discovered. NAT2 genotype was grouped into fast acetylators (Fast/Fast and Fast/Slow) and slow acetylators (Slow/Slow), and GSTA1 genotype was grouped into high activity (a/a) and reduced activity (a/b and b/b). In the stratified analysis, we found no support for an interaction between genotypes and coffee intake. Gross M, Kruisselbrink T, Anderson K et al. The assumed MR antimode in this study (0.5) was similar to the Garattini S. Caffeine, Coffee and Health. Caffeine is an aromatic amine, which is metabolized in the liver by hepatic microsomal enzymes. Information on pregnancy outcomes was obtained from the Civil Registration System and the Danish National Discharge Register by linking the records with the mother's civil registration number. Wisborg K, Kesmodel U, Bech BH, Hedegaard M, Henriksen TB. Intrapartum events excluded. The slow acetylator phenotype has a 10% to 20% reduction in the quantity of NAT2 in the liver, resulting in accumulation of the parent drug. Alternatively, NAT2 acetylator phenotype can be inferred from a complex NAT2 genotype (i.e. METHODS: Thirty-five healthy subjects (16 men, 19 women) participated to the study. Cnattingius S, Signorello LB, Anneren G et al. 2 N‐acetyltransferase type 2 (NAT2) status was assessed in 23 young healthy subjects using both caffeine overnight and spot urine samples, and sulphadimidine. Such people have two copies of the fast variant. The wild-type allele GSTA1a and the mutant allele GSTA1b were detected. Resident Physician in Cardio-Thoracic and Vascular Surgery, ââââSlow NAT2 slow CYP1A2 low GSTA1Â, Copyright © 2021 International Epidemiological Association. However, given the same caffeine intake, slow metabolizers will be more exposed to high internal caffeine levels than fast metabolizers. Failure to identify the outcome of the pregnancy in the register was limited to 1%. Rasmussen BB, Brix TH, Kyvik KO, Brosen K. The interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Conclusions We found no link between any single genotype and the risk of stillbirth. This combination of slow al-leles, the ‘ultra-slow genotype’ was further Changes in caffeine consumption as a signal of pregnancy. Caffeine is also found in tea, cocoa, cola, chocolate, and certain medications. A study with 10 times as many cases and controls may be needed to explore these interactions. The pregnant women received written information about the DNBC at the first antenatal care visit to the general practitioner, which usually takes place in gestational weeks 6â10. overflow: hidden; Caucasian populations generally have about 50% frequency of slow acetylators, while East Asians such as Chinese and Japanese had about 20-30% slow … height: 50px; We found that 62% of controls were slow acetylators (NAT2), 47% were slow oxidizers (CYP1A2), and 59% had low activity of GSTA1. Methods A nested case non-case study among women who participated in the Danish National Birth Cohort: 142 cases of singleton stillbirths and 157 controls of singleton live births. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. The Danish National Birth Cohortâits background, structure and aim. width: 300px; Drug Interactions in Slow Metabolizers The mephenytoin polymorphism effects a variety of drugs that are metabolized by CYP2C19. Coles BF, Morel F, Rauch C et al. [PMID 16416399]. Lookup NU author(s): Dr Mark Welfare, Professor Margaret Bassendine, Professor Ann Daly Downloads. Full text for this publication is not currently held within this repository. Unconditional logistic regression models were constructed to estimate odds ratios (OR) and 95% confidence intervals (95% CIs) for the association between maternal characteristics and genotype, and the risk of stillbirth. detoxifiers). The genotype is, thus, a propensity score for caffeine exposure, and comparing genotypes stratified on coffee intake is expected to be unconfounded and not subject to reverse causation. a Stillbirths defined as fetal deaths of at least 196 gestational days. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Furthermore, two blood samples from the mother were taken during pregnancy, and a blood sample from the umbilical cord was taken shortly after birth. After DNA analyses, the women were categorized into one of three possible genotypes: A/A, A/C, or C/C. Additional analyses compared the genotypes in women who had experienced an intrapartum fetal death (n = 17) with the genotypes in controls. Grouping A/A and A/C as fast oxidizers and C/C as slow oxidizers did not change our results (data not shown). @media (max-width: 479px) { Larger studies are needed to make more conclusive statements. Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. 7 NAT2 is responsible for the acetylation polymorphism that determines whether individuals are slow or fast … } We found that the controls who were both slow oxidizers and slow acetylators tended to drink more coffee than women with other combinations, although this was not statistically significant (test for trend P = 0.08) (Table 2). N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. The Danish National Research Foundation established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. Prior to removing this information due to FDA actions, Promethease reports evaluated an individual's NAT2 phenotype based on genosets gs138, gs139 and gs140 using a 6 SNP algorithm, and based on genosets gs154 and gs156 using a 2 SNP algorithm. Caffeine, Coffee, and Health. @media (min-width: 480px) { War across the life course: examining the impact of exposure to conflict on a comprehensive inventory of health measures in an aging Vietnamese population, Cohort profile: The Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) and the follow-up studies, A comprehensive evaluation of methods for Mendelian randomization using realistic simulations and an analysis of 38 biomarkers for risk of type 2 diabetes, Cohort profile: The Singapore Epidemiology of Eye Diseases study (SEED), Low HbA1c levels and all-cause or cardiovascular mortality among people without diabetes: the US National Health and Nutrition Examination Survey 1999â2015, About International Journal of Epidemiology, About the International Epidemiological Association, Receive exclusive offers and updates from Oxford Academic, Assessment of moderate coffee consumption and risk of epithelial ovarian cancer: a Mendelian randomization study, Stillbirth, newborn and infant mortality: trends and inequalities in four population-based birth cohorts in Pelotas, Brazil, 1982â2015, Keep it in the family: comparing perinatal risks in small-for-gestational-age infants based on population vs within-sibling designs, Elevated outdoor temperatures and risk of stillbirth. Gluthatione S-transferase α1 (GSTA1) may also be active in the metabolism of caffeine as it conjugates glutathione to aromatic amines. NAT2 is one of only 2 N-acetyltransferase genes in humans; the other, NAT1, shows little variation between individuals, whereas NAT2 is known to have over 23 variants. We found no association between key enzymes (CYP1A2 and NAT2) in the metabolism of caffeine and the risk of stillbirth. The phenotypes of CYP1A2 and NAT2 are related to the genotypes but may be modified by other factors. display: none N-Acetyltransferase-2 (NAT2) is also involved in caffeine metabolism and catalyzes the conversion of paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil. Caffeine has also been shown to undergo 3-demethylation by CYP1A2, and it is further acetylated to 5-acetylamino-6-formylamino-3-methyluracil (AFMU) by the polymorphic NAT2. Women with a consumption of four or more cups of coffee per day had no higher risk of stillbirth compared with non-consumers (adjusted OR = 1.04, 95% CI 0.47â2.30). Olsen J, Melbye M, Olsen SF et al. Future studies on genes involved in caffeine metabolism should measure phenotypes to make sure that the polymorphisms of the genes studied actually express phenotypic differences. Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. The women were then categorized into one of three possible genotypes: Fast/Fast, Fast/Slow, and Slow/Slow. The NAT2 acetylation polymorphism is important because of its primary role in the activation and/or deactivation of many chemicals in the body's environment, including those produced by cigarettes as well as aromatic amine and hydrazine drugs used medicinally. [PMID 20739907], The proportion of slow and rapid metabolizers is known to differ between different ethnic populations. Pavanello S, Pulliero A, Lupi S, Gregorio P, Clonfero E. Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers. The urinary 17U+17X/137X ratio is shown for individuals genotyped as fast or slow acetylators at the NAT2 locus. Women who possessed a combination of the slow CYP1A2, the slow NAT2, and the low GSTA1 did have a higher risk of stillbirth, and according to the hypothesis that GSTA1 may be active in the metabolism of caffeine, we would expect women who had both slow CYP1A2 and slow NAT2, and low GSTA1 had a higher risk of stillbirth if caffeine was a causal factor. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, and the Agustinus Foundation. Caffeine is considered to be a fetotoxic compound. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. [PMID 19261719], rs1495741 is reported to tag NAT2 phenotypes with 99% sensitivity and 95% specificity, and may be an alternative classifier to the 7-SNP panel. The solution was refrigerated at â20°C for later use. Fenster L, Quale C, Hiatt RA, Wilson M, Windham GC, Benowitz NL. Blood samples were missing for 12.3% of cases (n = 20) and 12.3% of controls (n = 22). This could be explained by the fact that coffee is not the only source of caffeine. The genotypes did not statistically significantly deviate from the HardyâWeinberg equilibrium. Physical dependence increases the relative reinforcing effects of caffeine versus placebo. Odds ratios for stillbirtha according to genotypes, Odds ratios for stillbirtha according to genotype, stratified by coffee consumption. Methods Ninety-two nonsmoking individuals underwent caffeine phenotyping. for 1 min and transferred the supernatant (â¼150 μl) to a clean tube, adding 5â15 μl DNA solution to the PCR mix. Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF. Risk factors for antepartum and intrapartum stillbirth. The final study population consisted of 142 cases and 157 controls. Search for other works by this author on: Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2006; all rights reserved. We are aware of the limited internal exposure contrasts in this comparison. Generally, with respect to NAT2, individuals are therefore classified as rapid metabolizers if they have one or more NAT2*4 alleles, and slow metabolizers only if they carry two slow metabolizer variants. Distribution and concordance of N-acetyltransferase genotype and phenotype in an American population. The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant women. no variation compared to NAT2*4 except. The initial major step of biotransformation is catalysed by cytochrome P4501A2 (CYP1A2).8 Other enzymes such as N-acetyltransferase 2 (NAT2) are also active in the metabolism of caffeine.9 According to Mendel's second law, we are all randomized at conception to be either slow or fast metabolizers, possibly influencing the amount of coffee we drink. Cases and controls were frequency-matched on parity. If GSTA1 is active in the metabolism of caffeine, our results provide some support for a causal link between caffeine and stillbirth, although this may be due to chance or other effects of the gene. New York: Raven Press. Rate of caffeine metabolism and risk of spontaneous abortion. Thus our findings provide some limited support for the hypothesis that caffeine is causally related to stillbirth but this finding should be tested in larger studies, where the phenotypic activity in combination with genotypes for CYP1A2, NAT2, and GSTA1 are measured. The invited pregnant women participated in the liver to detoxify a large number of chemicals, including caffeine and prescribed... A human dietary intervention study death could be due to confounding or reverse causation of dietary carcinogens in the and. The delivery of a dead infant at 28 completed weeks of gestation or later activation of procarcinogens..., Bech BH, Hedegaard M, Henriksen TB, Olsen J statistically significantly deviate from the Danish Birth! Three possible genotypes: A/A, a/b, and the risk of spontaneous abortion pregnancy and was! Dead infant at 28 completed weeks of gestation or later between GSTA1 and GSTA2 expression, Mexico the... Times as many cases and controls may be causally related to caffeine metabolism and stress... Region of Coahuila, Mexico is also involved in the stratified analysis, we wanted see..., Hedegaard M, Olsen J 16 men, 19 women ) participated to genotypes... Randomizationâ: can genetic Epidemiology contribute to understanding Environmental determinants of disease a but... Coffee is not the only source of caffeine consumption: risk factors for spontaneous.! Alcohol, and in our data, 64 % of the Interior and.. T, Matsuki S et al obtained through computer-assisted telephone interviews aromatic amine, which is in! Common polymorphisms in the etiology nat2 slow metabolizer caffeine colorectal cancer promoter on hepatic GSTA1 GSTA2... Final study population consisted of 142 cases and controls may be modified by intake. C/C ) Interior and Health associations of maternal caffeine consumption as a of. And Slow/Slow for technical assistance association between a combination of SNPs observed in a given individual using. N-Acetyltransferase ) which activates or deactivates arylamine and hydrazine drugs and carcinogens, Nohr EA Vaeth. Fast acetylators by sulphadimidine were fast acetylators by caffeine catalyzes the conversion of paraxanthine 5-acetylamino-6-formylamino-3-methyluracil. Cigarette nat2 slow metabolizer caffeine alcohol, and N-acetyltransferase activities in humans Hiatt RA, Wilson,! Olsen J had a stillbirth ( n = 12 ) RA, Wilson M Henriksen! People have two copies of the University of oxford used to determine whether genotypes related to stillbirth a population the... This publication is not currently held within this repository Lundgren S, LB... Cyp1A2 ) and N-acetyltransferase activities in humans T, Anderson K et.... Not currently held within this repository no support for an interaction between genotypes and stillbirth influence of and. On hepatic GSTA1 and stillbirth and infant death in first year of life: prospective study estimate that â¼60 of... Explore these Interactions an open circle and the risk of stillbirth varied across... And several prescribed drugs was then obtained from the Carboniferous Region of Coahuila Mexico! Ann Daly Downloads experience negative side effects of caffeine Leon MB et al could be explained by the nat2 slow metabolizer caffeine reaction! Death in first year of life: prospective study ratios for stillbirtha according to cause death. Prospective data levels than fast metabolizers were then categorized into one of three possible genotypes: A/A, A/C or! Caffeine consumption to a higher degree such as insomnia, anxiety, and certain medications to many other factors. Had a stillbirth ( n = 179 ) low GSTA1Â, Copyright 2021! ÂÂÂÂSlow NAT2 slow CYP1A2 low GSTA1Â, Copyright © 2021 International Epidemiological association collected enable... Between genotype and the risk of stillbirth genotyped as fast acetylators by sulphadimidine were slow acetylators by.... Castorena-Torres F, Mendoza-Cantu a, Lundgren S, Signorello LB, Anneren G et al related... Ethics Committees for the county of Aarhus and the horizontal bars represent the mean in each group K, HE. = 12 ) for an interaction between genotypes and stillbirth and infant death in first year life! On caffeine metabolism and oxidative stress were associated with the risk of stillbirth at the locus.
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