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PubMed2001

Genetic polymorphisms in the androgen receptor and type II 5 alpha-reductase genes in prostate enlargement.

PURPOSE: We examined the association of androgen receptor gene cytosine-adenine-guanine (CAG) repeat length and the 2 single nucleotide polymorphisms A49T and V89L in the type II 5 alpha-reductase gene with prostate enlargement measured as the weight of the surgically removed prostate. MATERIALS AND METHODS: A total of 68 men with a prostate weighing 80 gm. or greater were compared with 197 controls with a prostate weighing less than 80 gm. These men had undergone radical prostatectomy between 1992 and 1996. DNA was extracted from archival prostate tissue uninvolved with cancer and genotyped for 3 polymorphic markers. The effects of genetic variants and clinicopathological variables on prostate enlargement risk were estimated by logistic regression. RESULTS: The age adjusted odds ratio estimate of prostate enlargement risk in men with 23 or greater versus 20 or fewer CAG repeats was 0.41 (95% confidence interval 0.19 to 0.89). This risk reduction was consistently found when an alternative prostate enlargement definition and subject restriction were used. No consistent association with prostate enlargement risk was observed for A49T or V89L polymorphisms. CONCLUSIONS: Our finding further supports the hypothesis that the shorter CAG repeat length of the androgen receptor gene is related to prostate enlargement.

Adenine↗
PubMed1980

Two-dimensional gel electrophoresis of cattle plasma proteins: genetic polymorphism of an alpha 1-protease inhibitor.

Two-dimensional electrophoretic analysis of cattle plasma proteins was done by a first dimension separation in agarose gel (pH 5.0), followed by a second dimension in horizontal polyacrylamide gel (pH 9.0). This method resulted in improved and reproducible separation of many alpha- and beta-globulins. Three groups of alpha-globulins, designated Pi-1, Pi-2 and Pi-3, were found to inhibit the esterolytic activity of bovine trypsin and bovine chymotrypsin. Pi-2 showed appreciable inhibition only for trypsin and genetic polymorphism was observed for this protein. Family data supported the hypothesis that the three Pi-2 types observed were controlled by two codominant, autosomal alleles. The occurrence of a third Pi-2 allele was also postulated in some animals studied. The frequency of the most common allele, Pi-2s, ranged from 0.5-0.8 in the different breeds of cattle studied (Swedish Red and White, Friesian, Jersey, Charolais and Simmental). The post-transferrins Ptf-1 and Ptf-2 in cattle plasma were shown to be two different genetic systems.

Animals↗
PubMed2004

Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1).

The multidrug resistance (MDR1) gene product P-glycoprotein is a membrane protein that functions as an ATP-dependent efflux pump, transporting exogenous and endogenous substrates from the inside of cells to the outside. Physiological expression of P-glycoprotein in tissues with excretory or protective function is a major determinant of drug disposition and provides a cellular defense mechanism against potentially harmful compounds. Therefore, P-glycoprotein has significant impact on therapeutic efficacy and toxicity as it plays a key role in absorption of oral medications from the intestinal tract, excretion into bile and urine, and distribution into protected tissues such as the brain and testes. There is increasing interest in the possible role of genetic variation in MDR1 in drug therapy. Numerous genetic polymorphisms in MDR1 have been described, some of which have been shown to determine P-glycoprotein expression levels and substrate transport. Furthermore, some of these polymorphisms have an impact on pharmacokinetic and pharmacodynamic profiles of drug substrates and directly influence outcome and prognosis of certain diseases. This review will focus on the impact of genetic variation in MDR1 on expression and function of P-glycoprotein and the implications of this variation for drug therapy and disease risk.

Genes, MDR↗
PubMed2004

Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism.

Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many pharmacological and behavioral effects of ethanol. In particular, acetaldehyde has been suggested to contribute to alcohol abuse and alcoholism. In the present paper, we review current data on the role of acetaldehyde and ethanol metabolism in alcohol consumption and abuse. Ethanol metabolism involves several enzymes. Whereas alcohol dehydrogenase metabolizes the bulk of ethanol within the liver, other enzymes, such as cytochrome P4502E1 and catalase, also contributes to the production of acetaldehyde from ethanol oxidation. In turn, acetaldehyde is metabolized by the enzyme aldehyde dehydrogenase. In animal studies, acetaldehyde is mainly reinforcing particularly when injected directly into the brain. In humans, genetic polymorphisms of the enzymes alcohol dehydrogenase and aldehyde dehydrogenase are also associated with alcohol drinking habits and the incidence of alcohol abuse. From these human genetic studies, it has been concluded that blood acetaldehyde accumulation induces unpleasant effects that prevent further alcohol drinking. It is therefore speculated that acetaldehyde exerts opposite hedonic effects depending on the localization of its accumulation. In the periphery, acetaldehyde is primarily aversive, whereas brain acetaldehyde is mainly reinforcing. However, the peripheral effects of acetaldehyde might also be dependent upon its peak blood concentrations and its rate of accumulation, with a narrow range of blood acetaldehyde concentrations being reinforcing.

Acetaldehyde↗
PubMed1992

Cytochrome P450IIE1 genetic polymorphisms, racial variation, and lung cancer risk.

Cytochrome P450IIE1 is responsible for the activation of carcinogenic N-nitrosamines, benzene, urethane, and other low-molecular-weight compounds. Restriction fragment length polymorphisms (PstI and RsaI restriction enzymes) have been identified in the cytochrome P450IIE1 transcription regulatory region that may affect expression. This study describes the PstI and RsaI polymorphisms in different racial populations and in a case-control study of lung cancer. The allelic frequencies were markedly different in Japanese, African-Americans, and Caucasians: the PstI rare allele was present at a frequency of 2% in Caucasians, 5% in African-Americans, and 24% in Japanese (P < 0.05). For the RsaI rare allele, frequencies were 2% in Caucasians, 2% in African-Americans, and 27% in Japanese (P < 0.05). The assay was also applied to 128 individuals enrolled in a case-control study of lung cancer. Although limited in statistical power, the data indicate no evidence for an association in the aggregate of cytochrome P450IIE1 PstI [for which the odds ratio was 0.7 (95% confidence interval (C.I.) = 0.2-2.8)] or RsaI [for which the odds ratio was 0.9 (95% C.I. = 0.2-5.4)] restriction fragment length polymorphisms with lung cancer in this U.S. population. When analyzed by race, the lung cancer odds ratio for the PstI mutant allele in African-Americans was 0.19 (95% C.I. = 0.03-1.38), and in Caucasians it was 4.13 (95% C.I. = 0.34-48.8). For the RsaI mutant allele, the odds ratios were 0.20 (95% C.I. = 0.02-2.43) and 4.28 (95% C.I. = 0.35-50.6), respectively. The ethnic differences of these restriction fragment length polymorphisms might be related to genetic susceptibilities for lung cancer among Caucasians and for gastric or esophageal cancer among Japanese.

Alleles↗
PubMed2005

Human alpha class glutathione S-transferases: genetic polymorphism, expression, and susceptibility to disease.

The human alpha class glutathione S-transferases (GSTs) consist of 5 genes, hGSTA1-hGSTA5, and 7 pseudogenes on chromosome 6p12.1-6p12.2. hGSTA1-hGSTA4 have been well characterized as proteins, but hGSTA5 has not been detected as a gene product. hGSTA1-1 (and to a lesser extent hGSTA2-2) catalyzes the GSH-dependent detoxification of carcinogenic metabolites of environmental pollutants and tobacco smoke (e.g., polycyclic aromatic hydrocarbon diolepoxides) and several alkylating chemotherapeutic agents and has peroxidase activity toward fatty acid hydroperoxides (FA-OOH) and phosphatidyl FA-OOH. hGSTA3-3 has high activity for the GSH-dependent Delta(5)-Delta(4) isomerization of steroids, and hGSTA4-4 has high activity for the GSH conjugation of 4-hydroxynonenal. hGSTA4 is expressed in many tissues; hGSTA1-1 and hGSTA2-2 are expressed at high levels in liver, intestine, kidney, adrenal gland, and testis; and hGSTA3 is expressed in steroidogenic tissues. Functional, allelic, single nucleotide polymorphisms occur in an SP1-binding element of hGSTA1 and in the coding regions of hGSTA2 and hGSTA3. The main effects of these polymorphisms are the low hepatic expression of hGSTA1 in individuals homozygous for hGSTA1*B and the low specific activity of the hGSTA2E-2E variant toward FA-OOH. These properties suggest that alpha class GSTs will be involved in susceptibility to diseases with an environmental component (such as cancer, asthma, and cardiovascular disease) and in response to chemotherapy. Although hGSTM1, hGSTT1, and hGSTP1 have been associated with such diseases (on the basis of genetic polymorphisms as indicators of expression), alpha class GSTs have been little studied in this respect. Nevertheless, hGSTA1*B has been associated with increased susceptibility to colorectal cancer and with increased efficacy of chemotherapy for breast cancer. Methods for identification and quantitation of human alpha class GST protein, mRNA, and genotype are reviewed, and the potential for GST-alpha in plasma to be used as a marker for hepatic expression and induction is discussed.

Animals↗
PubMed1983

A genetic polymorphism of a human urinary mucin.

We report here a novel genetically determined polymorphism of a human urinary mucin which is demonstrable by the separation technique of SDS polyacrylamide gel electrophoresis, followed by detection with radio-iodinated lectins. The mucins are demonstrable using various lectins but the polymorphism is most easily recognized using peanut agglutinin and we therefore propose to designate this new genetic locus PUM (peanut-reactive urinary mucin). Four common alleles have been identified and an autosomal codominant mode of inheritance has been found in the families studied so far.

Alleles↗
PubMed2002

[Use of case-parents trio for epidemiological studies of association between genetic polymorphisms and complex diseases].

In case-control studies, spurious associations between allelic variants in candidate genes and disease may arise as a result of population stratification by ethnicity. In epidemiological terms, the ethnic group would act as a confounding factor if both the genotype frequency and the incidence/prevalence of a given chronic disease vary across ethnic groups. Population stratification is a key element in the study of population dynamics and the knowledge of the disparity in health-related conditions among strata has important social and public health implications. However, it would not be scientifically correct to conclude a causal gene-disease association in situations in which the association arises as a consequence of a particular population structure. Although the relevance and magnitude of the bias derived from this confounding, effect would be different depending on the population considered, there has been an increased use of study designs such as the case-parent study, that avoids the effect of population stratification by ethnicity. In this article, we review the analysis of case-parent trios using unrelated affected cases as an epidemiological study design for testing association between genetic polymorphisms and disease.

Alleles↗
PubMed2000

Genetic polymorphisms in ethanol metabolism: issues and goals for physiologically based pharmacokinetic modeling.

Chronic exposure to excessive ethanol consumption has adverse effects on virtually all organs and tissues in the body, including but not limited to the liver, pancreas, reproductive organs, central nervous system, and the fetus. Exposure to ethanol can also enhance the toxicity of other chemicals. Not all persons exposed to the same amount of ethanol experience the same degree of adverse effects. For example, only 12% to 13% of alcohol abusers develop cirrhosis. Possible factors which may alter susceptibility include age, sex, nutritional status, health status (i.e., smokers) and race. Some of these factors affect susceptibility because they alter ethanol metabolism, which occurs primarily in the liver by alcohol dehydrogenase (ADH). Genetic polymorphisms for ADH partially account for the observed differences in ethanol elimination rates among various populations but the relative contribution to susceptibility is not completely understood. Incorporation of the kinetic parameters associated with ADH polymorphisms into a physiologically based pharmacokinetic (PBPK) model for ethanol will aid in assessing the relative contribution to susceptibility. The specific information required to develop this model includes Km and Kcat values for each ADH isoform and the amount of each isoform present in the liver. Blood ethanol concentrations (BEC) from various populations with known ADH phenotypes are also necessary to validate the model. The impact of inclusion of these data on PBPK model predictions was examined using available information from adult white and African American males.

Alcohol Dehydrogenase↗
PubMed2004

Genetic polymorphism of epoxide hydrolase and glutathione S-transferase in COPD.

Genetic susceptibility to the development of chronic obstructive pulmonary disease (COPD) might depend on variation in the activities of enzymes that detoxify cigarette smoke products, such as microsomal epoxide hydrolase (mEPHX) and glutathione S-transferase (GST). It was investigated whether polymorphisms in these genes had any association with susceptibility to COPD and COPD severity. The genotypes of 184 patients with COPD and 212 control subjects were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis of the mEPHX, GSTM1, GSTT1 and GSTP1 genes. All subjects were smokers or exsmokers. The proportion of GSTM1-null genotypes was significantly higher in patients with COPD than in control subjects (61.4 versus 42.5%). No differences were observed in the frequency of polymorphic genotypes for mEPHX, GSTT1 and GSTP1. During combined analysis of genetic polymorphisms for mEPHX, GSTM1 and GSTP1, it was found that there are strong indicators for susceptibility to COPD (genotype combination with at least one mutant mEPHX exon-3 allele (histidine 113), GSTM1 null and homozygous for the GSTPI isoleucine 105 allele). The frequencies of homozygous mutant alleles of mEPHX exon 3 and the GSTMI-null genotype were significantly higher in patients with severe COPD (forced expiratory volume in one second of <35% of the predicted value). It is proposed that the combination of genetic variants including at least one mutant microsomal epoxide hydrolase exon-3 allele and glutathione S-transferase M1-null and homozygous isoleucine 105 glutathione S-transferase P1 genotypes are significant indicators of susceptibility to chronic obstructive pulmonary disease in the Taiwanese population. In addition, the homozygous variant of microsomal epoxide hydrolase exon 3 and the glutathione S-transferase M1-null genotype are independent risk factors for developing severe chronic obstructive pulmonary disease.

Case-Control Studies↗
PubMed2006

[Association of genetic polymorphisms in human leukocyte antigen-DQA1 with intrahepatic cholestasis of pregnancy in Chengdu district].

OBJECTIVE: To explore the relationship between human leukocyte antigen-DQA1 (HLA-DQA1) allele gene polymorphism and intrahepatic cholestasis of pregnancy (ICP). METHODS: Forty-five patients with ICP, eighteen ICP families, forty-five normal pregnant women and eighteen normal control families were tested for HLA-DQA1 allele gene polymorphism by polymerase chain reaction with sequence-specific primer (PCR-SSP) method. RESULTS: The frequency of HLA-DQA1*0301 in normal pregnant women was markedly higher than that in the ICP group (P>0.05). No significant differences were observed between the frequencies of other detected HLA-DQA1 alleles in both groups. The analysis of feto-maternal or couples sharing of the HLA-DQA1 alleles showed that no significant differences were observed between the two groups. CONCLUSION: The above findings suggest that there is no significant association between the genetic polymorphisms in HLA-DQA1 and ICP in Chengdu district; HLA-DQA1*0301 may be a protective gene against ICP. It may prevent the development of ICP.

Adult↗
PubMed2006

No association between the genetic polymorphisms in the RTN4R gene and schizophrenia in the Chinese population.

The RTN4R gene is located in the 22q11 region and it encodes a subunit of the receptor complex (RTN4R-p75NTR) which results in neuronal growth inhibitory signals in response to Nogo-66, MAG or OMG signaling. Previous studies have suggested that RTN4R might act as a potential candidate for schizophrenia susceptibility loci. We genotyped four SNPs within the gene and conducted a case-control study and TDT analysis, involving 707 schizophrenic patients, 689 controls and 372 unrelated small nuclear families with schizophrenic offspring in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in both family- and nonfamily-based samples. Our results suggest that there is no significant association between the genetic polymorphisms and schizophrenia in the Han Chinese population.

Case-Control Studies↗
PubMed1999

[Genetic polymorphism and susceptibility to occupational chronic manganism: a case-control study].

OBJECTIVE: In a case-control study, the possible genetic factors relevance to occupational chronic manganism were investigated. METHODS: Forty-nine manganisms who were welders and ferromanganese smelters occupationally exposed to manganese dust and fume from three metallurgical industries, and fifty unrelated healthy control subjects who were working same workshops were recruited. The subjects were matched for sex, age, cigarette and alcohol intake. The manganese exposure duration was also matched in this case-control study. Genetic polymorphism of cytochrome P450 2D6L (CYP2D6L) gene and NAD(P)H: quinone oxidreductase (NQO1) genes from all subjects were investigated. The mutations of CYP2D6L gene located exon 6 were analyzed by a polymerase chain reaction (PCR)-based DNA amplification combined with Hha I restriction fragment length polymorphism (RFLP). The substitution of 609(C-T) at exon 6 of DT-diaphroase gene was analyzed by PCR combined Hinf I RFLP. RESULTS: The frequency of polymorphic allels, a mutation of CYP2D6, was significantly lower in patients with manganism (16.3%) than that of the controls (29.0%). A significant association was also found between the homozygote variant of CYP2D6L gene and occupational manganism. These results suggest that the CYP2D6 gene might be one of the susceptibility genes for Mn-induced neurotoxicity. The allele and genotype frequencies of NQO1 gene were similar in the manganism cases and control subjects. CONCLUSION: It is possible that CYP2D6 gene may be a valuable susceptibility biomarker responded to Mn-induced central nervous system disorders in workers exposed to manganese.

Adult↗
PubMed2002

Genetic polymorphisms of drug-metabolizing enzymes and susceptibility to oral cavity cancer.

We investigated the association of polymorphisms of drug-metabolizing enzymes and susceptibility to oral cavity cancer. Polymerase chain reaction (PCR)-based analyses were performed on genomic DNA of 94 Caucasian patients in Germany and 92 healthy German controls to determine genotypes of polymorphisms in CYP1A1, GSTM1 and NAT2. For CYP1A1, the homozygous mutant genotype Val/Val did not occur. The heterozygous genotype Ile/Val (6.5% cases versus 4.3% controls) and the homozygous wild-type Ile/Ile (95.7% cases versus 93.5% controls) showed no statistically significant differences between groups (X(2)=0.47; P=0.534, Fisher's exact test, two-sided). The GSTM1 homozygous null genotype occurred more frequently in cancer patients (59.6%) compared to controls (53.3%) but this difference remained insignificant in X(2)-analysis (X(2)=1.07; P=0.587). Almost identical genotype distributions between cases and controls were found for all three NAT2 acetylators. Hence, these three genetic polymorphisms are unlikely to be associated with oral cavity cancer in the population studied.

Adult↗
PubMed2001

Clinical relevance of genetic polymorphisms in the human CYP2C subfamily.

The human CYP2Cs are an important subfamily of P450 enzymes that metabolize approximately 20% of clinically used drugs. There are four members of the subfamily, CYP2C8, CYP2C9, CYP2C19, and CYP2C18. Of these CYP2C8, CYP2C9, and CYP2C19 are of clinical importance. The CYP2Cs also metabolize some endogenous compounds such as arachidonic acid. Each member of this subfamily has been found to be genetically polymorphic. The most well-known of these polymorphisms is in CYP2C19. Poor metabolizers (PMs) of CYP2C19 represent approximately 3-5% of Caucasians, a similar percentage of African-Americans and 12-100% of Asian groups. The polymorphism affects metabolism of the anticonvulsant agent mephenytoin, proton pump inhibitors such as omeprazole, the anxiolytic agent diazepam, certain antidepressants, and the antimalarial drug proguanil. Toxic effects can occur in PMs exposed to diazepam, and the efficacy of some proton pump inhibitors may be greater in PMs than EMs at low doses of these drugs. A number of mutant alleles exist that can be detected by genetic testing. CYP2C9 metabolizes a wide variety of drugs including the anticoagulant warfarin, antidiabetic agents such as tolbutamide, anticonvulsants such as phenytoin, and nonsteroidal anti-inflammatory drugs. The incidence of functional polymorphisms is much lower, estimated to be 1/250 in Caucasians and lower in Asians. However, the clinical consequences of these rarer polymorphisms can be severe. Severe and life-threatening bleeding episodes have been reported in CYP2C9 PMs exposed to warfarin. Phenytoin has been reported to cause severe toxicity in PMs. New polymorphisms have been discovered in CYP2C8, which metabolizes taxol (paclitaxel). Genetic testing is available for all of the known CYP2C variant alleles.

Alleles↗
PubMed2003

An association between NQO1 genetic polymorphism and risk of bladder cancer.

NAD(P)H:quinone oxidoreductase (NQO1) is a detoxification enzyme that plays a critical role in protecting cells against chemically induced oxidative stress, cytotoxicity, mutagenicity, and carcinogenicity. NQO1 protects cells from oxidative damage by preventing the generation of reactive oxygen species and reducing certain environmental carcinogens, such as nitroaromatic compounds, heterocyclic amines, and possible cigarette smoke condensate. A C-->T single nucleotide polymorphism in exon 6 was shown to reduce NQO1 enzyme activity, which may diminish the protection provided by NQO1. Therefore, we hypothesized that people with the variant allele genotypes of NQO1 are at higher risk for bladder cancer. In an ongoing case-control study, the NQO1 genotypes were successfully identified by polymerase chain reaction restriction fragment length polymorphism in 265 bladder cancer patients and 261 control subjects matched for age, sex, and ethnicity. The frequency of the variant NQO1 allele was 18% for controls and 21% for cases. The variant allele genotypes of NQO1 were associated with a higher risk of bladder cancer in Caucasians (odds ratio (OR)=1.51; 95% confidence interval (CI)=1.01-2.25). Further analysis in Caucasians showed an elevated bladder cancer risk in men (OR=1.75; 95% CI=1.08-2.85) but not in women (OR=1.16; 95% CI=0.57-2.37). In addition, the variant allele genotypes were associated with higher bladder cancer risk in ever smokers (OR=1.78; 95% CI=1.06-3.00), but not in never smokers (OR=1.19; 95% CI=0.65-2.20). These results suggest that the NQO1 genetic polymorphism modulates bladder cancer risk, especially in men and ever smokers.

Aged↗
PubMed1999

Strain differences of rats in the susceptibility to aberrant crypt foci formation by 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine: no implication of Apc and Pla2g2a genetic polymorphisms in differential susceptibility.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine contained in cooked food, induces colon tumors in F344 male rats when administered orally. In the present study, PhIP was introduced to various rat strains, and susceptibility to the induction of aberrant crypt foci (ACFs) was analyzed as a biomarker for colon carcinogenesis. BUF/Nac rats were highly susceptible, giving rise to 12.2 +/- 1.7 ACFs per rat. F344 rats were intermediate and ACI/N rats were resistant, giving 3.5 +/- 1.8 and 0.9 +/- 0.7 ACFs per rat, respectively. In spite of this, the extent of DNA damage by PhIP in F344, in terms of the level of PhIP-DNA adducts, was significantly lower than that in ACI/N. The differences in formation of ACFs could be, in some part, implicated in the differential susceptibility to colon carcinogenesis induced by PhIP, especially in a step later than adduct formation. In an attempt to determine the genetic factors implicated in the susceptibility to formation of ACFs, a possible involvement of the adenomatous polyposis gene (Apc) and its modifier secretory phospholipase A2 (Pla2g2a) was analyzed. No genetic polymorphisms in either Apc or Pla2g2a showed a significant correlation to susceptibility to formation of ACFs among rat strains.

Animals↗
PubMed2006

Effect of NAT1 and NAT2 genetic polymorphisms on colorectal cancer risk associated with exposure to tobacco smoke and meat consumption.

N-Acetyltransferases 1 and 2 (NAT1 and NAT2), both being highly polymorphic, are involved in the metabolism of aromatic and heterocyclic aromatic amines present in cigarette smoke and red meat cooked by high-temperature cooking techniques. We investigated the effect of differences in acetylation capacity, determined by NAT1 and NAT2 genotypes, on colorectal cancer risk associated with exposure to tobacco smoke or red meat consumption. In this population-based case-control study in Germany, 505 patients with incident colorectal cancer and 604 age- and sex-matched control individuals with genotyping data and detailed risk factor information were included. Genotyping of NAT1 and NAT2 genetic polymorphisms was done using a fluorescence-based melting curve analysis method. The association between genotypes, environmental exposures, and colorectal cancer risk was estimated using multivariate logistic regression. Colorectal cancer risk associated with active smoking was elevated after accumulation of 30(+) pack-years of smoking [odds ratio (OR), 1.4; 95% confidence interval (95% CI), 0.9-2.2] but not significantly modified by either NAT1 or NAT2 genotype. Exposure to environmental tobacco smoke was associated with an increased risk for colorectal cancer only among NAT2 fast acetylators (OR, 2.6; 95% CI, 1.1-5.9 for exposure in childhood and adulthood). Frequent consumption of red meat significantly increased colorectal cancer risk for the group comprising all NAT2 fast acetylators or carriers of the NAT1*10 allele (OR, 2.6; 95% CI, 1.1-6.1) but not among those with "slow" NAT1 and NAT2 genotypes. Our findings indicate that NAT1 and NAT2 genotypes may contribute jointly to individual susceptibility and that heterocyclic aromatic amines may play an important role in colorectal cancer associated with red meat and possibly also exposure to environmental tobacco smoke.

Acetylation↗

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