Chida M, Yokoi T, Fukui T, Kinoshita M, Yokota J, Kamataki T. Detection of three genetic polymorphisms in the 5'-flanking region and intron 1 of human CYP1A2 in the Japanese population. margin: 0 auto; In the stratified analysis, we found no support for an interaction between genotypes and coffee intake. The genotypes did not statistically significantly deviate from the Hardy–Weinberg equilibrium. Background Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase 2 (NAT2) are key enzymes in the metabolism of caffeine. 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). } We did, however, observe that subjects with a combination of slow CYP1A2, slow NAT2, and low GSTA1 genes had almost a 2-fold risk of stillbirth compared with subjects with other combinations of genotypes. 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. Drug Interactions in Slow Metabolizers The mephenytoin polymorphism effects a variety of drugs that are metabolized by CYP2C19. 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. N-Acetyltransferase-2 (NAT2) is also involved in caffeine metabolism and catalyzes the conversion of paraxanthine to 5-acetylamino-6-formylamino-3-methyluracil. 17960 Ensembl ENSG00000156006 ENSMUSG00000025588 UniProt P11245 P50294 RefSeq (mRNA) NM_000015 NM_008673 RefSeq (protein) NP_000006 NP_032699 Location (UCSC) Chr 8: 18.39 – 18.4 Mb n/a PubMed search Wikidata View/Edit Human View/Edit Mouse N-acetyltransferase 2 (arylamine N-acetyltransferase), also known as NAT2, is an enzyme which in humans is encoded by the NAT2 … NAT2 may also refer to SLC38A1 . The final study population consisted of 142 cases and 157 controls. 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. N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. The women were categorized into one of three possible genotypes: a/a, a/b, and b/b. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Recent publications report an association between coffee or caffeine intake during pregnancy and the risk of spontaneous abortion and stillbirth,2–6 but very few of these associations are causal. This page was last edited on 8 January 2020, at 00:55. https://www.SNPedia.com/index.php?title=NAT2&oldid=1690258, N-acetyltransferase 2 (arylamine N-acetyltransferase), NAT2*4: considered to be the wild-type allele, and the exemplar rapid metabolizer; consists of the first nucleotide shown in the "aka" (also known as) names listed above for these seven, NAT2*6B: 590A (only), i.e. slow acetylators by sulphadimidine were fast acetylators by caffeine and four subjects classed as fast acetylators by sulphadimidine were slow acetylators by caffeine. This was also found by Nordmark et al.31 who studied the influence of CYP1A2 genotype on the CYP1A2 activity in pregnant women. Cnattingius S, Signorello LB, Anneren G et al. Coffee consumption is related to many other lifestyle factors that cannot fully be adjusted for. Slow acetylators or slow oxidizers had the same risk of stillbirth as fast acetylators or oxidizers, (OR = 0.95, 95% CI 0.60–1.51 and OR = 1.06, 95% CI 0.67–1.67, respectively) (Table 3). Methods Ninety-two nonsmoking individuals underwent caffeine phenotyping. AIMS: (i) To compare the phenotyping of healthy subjects for NAT2 and CYP1A2 activities with caffeine, by the simultaneous assay of the urinary metabolites AFMU and AAMU, and (ii) to ascertain whether NAT2 and CYP1A2 phenotyping is influenced by the use of AFMU or AAMU in the metabolite ratio. Cases included all women who had a stillbirth (n = 179). Caffeine is an aromatic amine, which is metabolized in the liver by hepatic microsomal enzymes. Nordmark A, Lundgren S, Ask B, Granath F, Rane A. Kalow W, Tang BK. 5 CYP1A2 is involved in the metabolism of numerous drugs 4,6 and is an activator of procarcinogens. CYP2C19 NAT2 Caucasians Asians Prevalence (%) Slide 6 Slow Metabolizers –Prevalence Some genetic polymorphisms of drug metabolism exist in a substan tial portion of the population. Caffeine as a metabolic probe: exploration of the enzyme-inducing effect of cigarette smoking. 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. However these analyses have limited power as indicated by the wide CIs. Furthermore, the amount of coffee drunk may be modified by a coffee aversion or pregnancy nausea, which correlates with hormone levels of significance for fetal survival.7 The association may thus reflect confounding or reverse causation. For the combined genotype (slow CYP1A2, slow NAT2, and low GSTA1), we found a higher risk of stillbirths (however, CIs included unity) also among non-consumers of coffee. Slow NAT2 acetylators have an increased risk of drug-induced hepatotoxicity. The genotypes were dichotomized for the analyses. Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF. Information on exposures during pregnancy was obtained through computer-assisted telephone interviews. This work was supported by a grant from the Danish Centre for Environmental Health, Danish Ministry of the Interior and Health. Sachse C, Bhambra U, Smith G et al. Women with a low activity of GSTA1 had a higher risk of stillbirth (OR = 1.42, 95% CI 0.88–2.28), but CIs included unity. Scholl TO, Stein TP. Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. Furthermore, two blood samples from the mother were taken during pregnancy, and a blood sample from the umbilical cord was taken shortly after birth. } a combination of SNPs observed in a given individual) using the publicly-accessible web-server NAT2PRED (http://nat2pred.rit.albany.edu). Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. Common polymorphisms in the N-acetyltransferase-2 (NAT2) metabolic enzyme determine slow or rapid acetylator phenotypes. .myheritage_health_ad_container .myheritage_ad_mobile { Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. • A 48-year-old woman with isoniazid-associated hepatotoxicity was heterozygous for two gene variants, C481T and G857A, in the N-acetyltransferase 2 (NAT2) gene, also known as NAT2*5A and NAT2*7A/B haplotypes. Caffeine intake and the risk of first-trimester spontaneous abortion. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Coffee and fetal death: a cohort study with prospective data. Slow CYP1A2 and NAT2 vs other combinations 0.29 0 152 1.11 (0.52–2.37) ½–3 92 2.08 (0.84–5.12) 4+ 55 0.69 (0.23–2.08) All 299 1.23 (0.74–2.05) Slow CYP1A2 and NAT2 and low GSTA1 vs other combinations 0.42 0 151 1.71 (0.68–4.29) ½–3 92 Results The median ratio for urinary 17 U+17X/137X was 6.7 (range 1.45-18.65). 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. 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. @media (max-width: 479px) { We did not find any consistent pattern of higher risk among slow metabolizers of caffeine at any level of coffee use (Table 4). Rate of caffeine metabolism and risk of spontaneous abortion. In this report, we describe a metabolic phenotyping procedure that can be used to determine concomitantly the hepatic CYP1A2 and NAT2 phenotypes. NAT2 slow metabolizers are more prone to the side effects of polymorphically acetylated drugs, as is the SLE-like syndrome induced by hydralazine and procainamide, the side effects due to sulphasalazine and the skin rash secondary to many sulphonamides. The women were then categorized into one of three possible genotypes: Fast/Fast, Fast/Slow, and Slow/Slow. 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. Neither the NAT2 slow acetylator phenotype nor any of the ESR1 or ESR2 polymorphisms in this study were associated with an increased risk of PD (Table 2, Table 3). Coles BF, Morel F, Rauch C et al. 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. 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. We randomly sampled a similar number of control women with a singleton live birth. 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. Odds ratios for stillbirtha according to genotypes, Odds ratios for stillbirtha according to genotype, stratified by coffee consumption. Individuals can be classified as either rapid, or slow, metabolizers (i.e. We found no association between slow oxidizers (CYP1A2) or slow acetylators (NAT2) and the risk of stillbirth, when studying single nucleotide polymorphisms. After removing the washing buffer, we added 200 μl 5% Chelex-100 and incubated the sample at 60°C for 30 min and 100°C for 30 min. HIF-1α Stimulators Function Equally to Leading Hair Loss Agents in Enhancing Dermal Papilla Growth. Fenster L, Quale C, Hiatt RA, Wilson M, Windham GC, Benowitz NL. Maternal consumption of coffee during pregnancy and stillbirth and infant death in first year of life: prospective study. High levels of coffee intake correlate with a number of other lifestyle factors and coffee intake is influenced by pregnancy conditions. Resident Physician in Cardio-Thoracic and Vascular Surgery,     Slow NAT2 slow CYP1A2 low GSTA1Â, Copyright © 2021 International Epidemiological Association. The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans. We stratified the analysis of genotypes on coffee intake to see whether the association between genotype and stillbirth was modified by coffee intake. Coffee or caffeine exposure has been related to stillbirth. The urinary 17U+17X/137X ratio is shown for individuals genotyped as fast or slow acetylators at the NAT2 locus. Alleles are according to Mendel's second law randomly distributed at conception. [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. [PMID 10667461] Drugs reported to be metabolized by NAT2 include isoniazid, sulfadimidine, hydralazine, dapsone, procaine amide, sulfapyridine, nitrazepam and some sulfa drugs. For the genotyping of NAT2 we used the method described by Sachse et al.14 PCR products were digested by the restriction enzymes Taq, Dde, Kpn, and Bam. Fenster et al. Women with missing information on coffee intake were excluded from the study (n = 12). In: Garattini S (ed.). We found that 62% of controls were slow acetylators (NAT2), 47% were slow oxidizers (CYP1A2), and 59% had low activity of GSTA1. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. normal) metabolizer variants as well, such as: As mentioned above, individuals running the Promethease program associated with SNPedia used to be automatically tested for NAT2 genotype via the genosets known as gs138, gs139 and gs140. Wen W, Shu XO, Jacobs DR Jr, Brown JE. [PMID 3712391]. Garattini S. Caffeine, Coffee and Health. We only have information on the consumption of tea, and in our data, 64% of non-coffee drinkers do drink tea daily. However, women with a combination of slow CYP1A2, slow NAT2, and low GSTA1 had almost a 2-fold risk of stillbirth compared with women without this combination (OR = 1.86, 95% CI 1.02–3.37) (Table 3). .myheritage_health_ad_container .myheritage_ad_desktop { Metabolism of caffeine and other components of coffee. }. Gluthatione S-transferase α1 (GSTA1) conjugates glutathione to aromatic amines and protects against oxidative stress, which also has been associated with adverse pregnancy outcomes.10 We hypothesize that because caffeine is an aromatic amine, GSTA1 may be active in the metabolism of caffeine. 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. 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. height: 50px; Wisborg K, Kesmodel U, Bech BH, Hedegaard M, Henriksen TB. 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. Our aim was to determine whether genotypes related to caffeine metabolism and oxidative stress were associated with the risk of stillbirth. Variability in NAT2 activity (as determined by caffeine AFMU/AFMU+1X+1U ratio) between different populations exists - significantly higher NAT2 activity is observed in Koreans compared to Swedes, and this may be due to a higher proportion of the NAT2 *4 rapid allele in Koreans and the higher frequency of slow acetylator genotype in Swedes [Article:22105431]. Arnaud MJ. Intrapartum events excluded. However, the combination of acetylator and oxidizer polymorphisms (slow/slow) showed a moderate but not statistically significant increased risk of stillbirth. 7 NAT2 is responsible for the acetylation polymorphism that determines whether individuals are slow or fast … 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 1999–2015, 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, 1982–2015, 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. Alternatively, NAT2 acetylator phenotype can be inferred from a complex NAT2 genotype (i.e. Caffeine is also found in tea, cocoa, cola, chocolate, and certain medications. Visit https://www.reddit.com/r/SNPedia, .myheritage_ad_mobile { Caucasian populations generally have about 50% frequency of slow acetylators, while East Asians such as Chinese and Japanese had about 20-30% slow … 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. There is also evidence linking slow metabolizers with an increased risk of having a nonfatal heart attack and/or high blood pressure with higher amounts of coffee intake(6,7). 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. Castorena-Torres F, Mendoza-Cantu A, de Leon MB et al. Caffeine is considered to be a fetotoxic compound. overflow: hidden; Second, we wanted to see whether slow caffeine metabolizers had a higher risk of stillbirth, taking the external coffee intake into account. The associations of maternal caffeine consumption and nausea with spontaneous abortion. The Danish National Research Foundation established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The interaction was evaluated by a likelihood ratio test. Rasch V. 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