CYP1A1, cigarette smoking, and colon and rectal cancer

Cytochrome P-450 (CYP) is involved in the activation and metabolism of polycyclic aromatic hydrocarbons in tobacco products. The authors evaluated the association of two polymorphisms in the CYP1A1 gene--the noncoding Msp I polymorphism in the 3'-untranslated region and the Ile462Val polymorphism in exon 7--with colon and rectal cancer. The authors used data from two incident case-control studies of colon cancer (1,026 cases and 1,185 controls) and rectal cancer (820 cases and 1,036 controls) conducted in California and Utah (1991-2002). CYP1A1 genotype was not associated with colon or rectal cancer. Having GSTM1 present, a CYP1A1 variant allele, and the rapid-acetylator NAT2 imputed phenotype was associated with increased risk of colon cancer (odds ratio = 1.7, 95% confidence interval: 1.2, 2.3). Among men, the greatest colon cancer risk was observed for having any CYP1A1 variant allele and currently smoking (odds ratio = 2.5, 95% confidence interval: 1.3, 4.8; Wald chi(2)test: p < 0.01). Assessment of GSTM1 and CYP1A1 and rectal cancer in men showed a twofold elevation in risk for more than 20 pack-years of smoking, except among those with GSTM1 present who had a variant CYP1A1 allele. These data support the association between smoking and colon and rectal cancer. Smoking may have a greater impact on colorectal cancer risk based on CYP1A1 genotype; this might further be modified by GSTM1 for rectal cancer risk.     

Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of colorectal cancer

Environmental factors such as smoking cigarette, diets and alcohol may interact with genetic factors, which put one individual at a greater or lesser risk of a particular cancer than another. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. Many pieces of research have focused on the relationship between the distribution of polymorphic variants of different forms of the metabolic enzymes and colorectal cancer susceptibility because of importance roles of the metabolic enzymes in the activation of many procarcinogens or chemicals. In this respect five groups of the metabolic enzymes, cytochrome P450 (CYP) 1A1/CYP1A2, glutathione S-transferases (GSTs), N-acetyltransferases (NATs), aldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR), have been discussed here. A positive association between development of colorectal cancer and the mutant homozygous genotype in Msp1 polymorphism of CYP1A1 gene has been reported in Japanese in Hawaii. The relation between genetic polymorphisms in GSTs and cancer risk has also taken an interest. At least nine studies have demonstrated the relation between the GST polymorphisms and colorectal cancer. Two of these studies suggested an increased risk of approximately 2-fold among those with the GSTM1 null genotype, while others found no risk increase. None of these studies examined the combined effect of CYP1A1 and GST polymorphisms. Either NAT2 or CYP1A2 alone have been slightly associated with colorectal cancer. When CYP1A2 and NAT2 phenotype were combined, a significant increased risk (odds ratio of 2.8) was seen among well done meat consumers with the rapid-rapid phenotype. Two published studies have found that the risk of colorectal cancer can be enhanced (2-3 fold) in alcohol drinkers with heterozygous genotype of ALDH2 in two Japanese populations recently. Findings from three published studies suggested that the mutant genotype of MTHFR inversely slightly associated with colorectal cancer. Although some of genetic polymorphisms discussed here have not shown statistically significant increase/decrease in risk, individuals with differing genotypes may have different susceptibilities to colorectal cancer, based on environmental factors. Further studies are needed to identify risk groups more specific and to determine factors of importance in colorectal cancer development.     

CYP17、CYP19、SULT1A1基因多态性与汉族女性乳腺癌易感性的研究

目的探讨雌激素代谢酶CYP17、CYP19、SULT1A1基因多态性与女性乳腺癌易感性的关系.方法采用聚合酶链反应-限制性片段长度多态性及短臂重复多态性方法,检测213例乳腺癌患者和430名正常对照CYP17、CYP19、SULT1A1基因多态性分布;应用logistic回归等方法分析单个基因、多个基因联合及雌激素暴露因素对乳腺癌的危险度.结果CYP17变异等位基因A2病例组的频率为49.8%,对照组为49.1%,差异无统计学意义（P＞0.05）;SULT1A1变异等位基因His病例组的频率为13.6%,高于对照组的频率9.5%,差异有统计学意义（P=0.03）;CYP19（TTTA）10等位基因病例组的频率为12.4%,对照组为8.2%（P=0.02）;多基因模型分析显示,携带多个高危险基因显著增加患乳腺癌的危险性（趋势P=0.05）;多因素分析显示,携带SULT1A1 His及CYP19（TTTA）10等位基因与乳腺癌危险性相关;高雌激素暴露因素如累计行经年数长、初潮年龄早以及体重指数、腰臀比高等均为乳腺癌的危险因素.结论参与雌激素合成与代谢的多个酶基因多态性与乳腺癌的发生有关.     

Evaluation of Breast Cancer Risk in a Multigenic Model Including Low Penetrance Genes Involved in Xenobiotic and Estrogen Metabolisms

Breast cancer has become the most frequent cancer among women in Westernized countries. The majority of breast cancers are due to low penetrance genes, which can act with environmental factors, particularly nutrition. Polymorphisms in gene coding for xenobiotic and estrogen metabolic pathways could increase individual cancer susceptibility and lead to the indication of individuals at higher cancer risk. A population-based, case-control study consisting of 911 breast cancer cases and 1,000 healthy control cases was performed. The association between 11 single nucleotide polymorphisms (SNP) in 7 genes and breast cancer risk was investigated in a multigenic model. The CYP1B1-432 Leu-Val and Val-Val genotypes significantly increased risk [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08–1.39; OR = 1.51, 95% CI = 1.17–1.94, respectively] similarly as observed with CYP1B1-453 (Asn-Ser genotype: OR = 1.17, 95% CI = 1.00–1.37; Ser-Ser genotype: OR = 1.38, 95% CI = 1.00–1.89). We showed that catechol-O-methyltransferase (COMT) could modulate the risk conferred by CYP1B1, ESR, GSTP1, and NAT2 acetylation phenotype. Additionally, a higher risk conferred by the variant for COMT was noted only for individuals presenting a high waist-to-hip ratio (COMT Val-Met, OR = 1.60, 95% CI = 1.04–2.44; COMT Met-Met, OR = 1.57, 95% CI = 0.98–2.53), suggesting a relationship with abdominal adiposity. In conclusion, COMT constitutes a crucial element in estrogen metabolism by regulating carcinogen metabolites elimination and, consequently, is a major factor in breast cancer risk.     

代谢酶基因多态性与结直肠癌易感性关系的病例对照研究

目的以自然随访人群为研究对象，研究Ⅰ、Ⅱ相代谢酶基因多态性与结直肠癌（CRC）易感性的关系。方法采用聚合酶链反应（PCR）-限制性片段长度多态性（RFLP）、等位基因特异性PCR（AS-PCR）和多重PCR分析技术，检测140例CRC患者和343名健康对照细胞色素P450氧化酶CYP1A16235T／C、CYP1A2734C／A、CYP2E1—12596／C和-1019C／T各位点多态性，谷胱甘肽转移酶GSTMu（GSTM1）和GSTTheta（GSTT1）缺陷型，以及N-乙酰基转移酶基因NAT1和NAT2各等位基因型分布频率，分析其对CRC易感性的影响。结果等位基因CYP1A16235C、CYP1A2734A、CYP2E1—1259C、CyP2E1—1019T、GSTM1缺陷型、GSTT1缺陷型、NAT1＊10和NAT2Mx（x=1，2，3）的分布频率在病例组依次为31．65％、63．77％、23．02％、32．61％、57．25％、17．39％、26．45％和39．21％，对照组依次为39．85％、66．62％、20．27％、28．61％、55．46％、20．35％、25．22％和39．36％，所有基因型分布均符合Hardy—Weinberg平衡定律。单基因、多基因联合分层分析表明，CYP1A16235CC突变纯合型可显著降低CRC风险（OR=0．79，95％CI=0．63～0．99）；在携带CYP1A2734A等位基因个体，CYP1A16235C等位基因也可显著降低CRC风险（OR=0．53．95％CI：0．34～0．83）；在GSTT1缺陷型个体，GSTM1缺陷型可使机体罹患CRC的风险显著升高（OR=4．41，95％CI=1．21～16．10）。结论CYP1A16235C等位基因、GSTM1和T1缺陷基因型可影响机体对CRC的遗传易感性，前者是CRC的保护因素，后两者可使机体罹患CRC的风险增高。     

代谢酶基因多态性与结直肠癌的易感性

目的研究代谢酶细胞色素P450（cytochrome P450s,CYP）1A1、谷胱甘肽转移酶（glutathione—S-transferase,GST）M1和T1、尿苷二磷酸葡萄糖醛酸转移酶（UDPglucumnosyltransferase,UGT）1A7基因多态性与结直肠癌的易感性及其交互作用。方法2002年5月在浙江省嘉善县开展的现场病例对照研究及单纯病例研究,获得140例结直肠癌患者和343名健康对照,用PCR-限制性片段长度多态性等方法检测CYP1A1、GSTM1、GSTT1和UGT1A7的基因多态,并应用非条件logistic回归方法进行数据分析。结果CYPIA1 MspI多态（非编码区T6235C）C／C基因型、T／C和C／C基因型者相对于T／T基因型者的OR值分别为0．493（95％CI：0．254—0．956）和0．638（95％CI：0．427—0．952）,具有统计学意义;GSTM1、GSTT1非缺陷型与缺陷型的分布频率对照组和病例组比较差异无统计学意义;对照组和病例组UGT1A7变异／变异型基因与野生纯合型基因比较差异有统计学意义（OR=2．501,95％CI：1．456—4．296）。单纯病例研究分析,CYP1A1与GSTT1、GSTM1与GSTT1对结直肠癌的发生存在交互作用,COR值分别为2．617（95％CI：1．015—6．752）和3．935（95％CI：1．323—11．706）;而CYPlAl与GSTM1、CYP1A1与UGT1A7之间无交互作用。结论CYP1A1 MspI变异型可降低机体对结直肠癌的易感性,而UGT1A7的变异／变异基因型可增加结直肠癌的罹患风险,CYP1A1与GSTT1、GSTM1与GSTT1对结直肠癌的发生存在交互作用。     

Occupation, smoking, and the risk of high-grade invasive bladder cancer in Missouri.

Numerous epidemiological studies have established that occupational exposures and smoking are the two major known risk factors for the development of bladder cancer. Using data from the Missouri Cancer Registry, we investigated the hypothesis that individuals with occupationally-related bladder cancer are more likely to have a more invasive form of the disease. Data were analyzed for 2,893 white males diagnosed with primary bladder cancer in Missouri between 1984 and 1988. Of the 1,415 cases whose occupational status was recorded, 236 (17%) were employed in high-risk occupations. Cases with high-grade disease were more likely to have been employed in a high-risk occupation, after adjustment for age and smoking (adjusted odds ratio [AOR] = 1.7, 95% confidence interval [CI] = 1.1-2.6). High-risk workers under 60 years of age were most at risk for developing high-grade bladder tumors (AOR = 2.3, 95% CI = 1.0-5.3). There was no overall association between high-risk occupation and late-stage disease (AOR = 1.1, 95% CI = 0.7-1.5), but it was present in the men younger than 60 years of age (AOR = 2.0, 95% CI = 1.0-3.8). No association was found between tobacco use and grade (AOR = 1.1, 95% CI = 0.8-1.5), but cases with late-stage disease were more likely to be smokers (AOR = 1.5, 95% CI = 1.1-1.9). When occupations were examined individually, motor vehicle operators, truck drivers, vehicle mechanics, other mechanics, and janitors were among those most likely to be diagnosed with high-grade or late-stage tumors. Although further studies are necessary to confirm these results, they suggest that surveillance and targeted screening of workers in high-risk occupations may result in a greater yield of early invasive cancers and possibly decrease the mortality associated with this disease.     

N-acetyltransferase 2 polymorphisms, tobacco smoking, and breast cancer risk in the breast and prostate cancer cohort consortium

Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989-2006) in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions.     

Serum carotenoids, retinol, and tocopherols, and colorectal cancer risk in a Japanese cohort: effect modification by sex for carotenoids

To examine associations of serum carotenoids, retinol, and tocopherols with colorectal cancer risk, we conducted a case-control study nested within the Japan Collaborative Cohort Study. These micronutrients were measured in prediagnostic serum samples from 116 men and women who developed colorectal cancer during an 8-yr follow-up period and from 298 matched controls. In men, the higher level of serum total carotenoids was associated with a decreased risk: The multivariate-adjusted odds ratio (OR) for the highest vs. the lowest tertile was 0.34 (95% confidence interval [CI] = 0.11-1.00; trend P over tertiles = 0.040). In women, the higher levels of alpha- and and total carotenoids were instead related to an increased risk: The corresponding ORs were 4.72 (95% CI = 1.29-17.3), 2.00 (0.70-5.73), and 2.47 (0.73-8.34), respectively (trend P = 0.007, 0.040, and 0.064, respectively). We also found a somewhat decreasing risk with increased serum retinol in all subjects and alpha-tocopherol in men: The ORs (95% CI) for the highest tertiles were 0.29 (0.11-0.78; trend P over tertiles = 0.010) and 0.29 (0.07-1.17; trend P = 0.098), respectively. The effects of some carotenoids on colorectal cancer risk may be modified by sex or by factors associated with sex, including smoking and drinking habits.     

Joint effects of the N-acetyltransferase 1 and 2 (NAT1 and NAT2) genes and smoking on bladder carcinogenesis: a literature-based systematic HuGE review and evidence synthesis

Bladder cancer is an increasingly important international public health problem, with over 330,000 new cases being diagnosed each year worldwide. In a systematic review and evidence synthesis, the authors investigated the joint effects of the N-acetyltransferase genes NAT1 and NAT2 and cigarette smoking on bladder carcinogenesis. Studies were identified through an exhaustive search of multiple electronic databases and reference lists and through direct contact with study authors and experts. Random-effects meta-analysis was used within a Bayesian framework to investigate individual effects of NAT1 and NAT2 acetylation status on bladder cancer risk, while a novel approach was used to investigate joint effects of these two genes with cigarette smoking. An increased risk of bladder cancer was found in NAT2 slow acetylators (odds ratio = 1.46, 95% credible interval (CI): 1.26, 1.68) but not in NAT1 fast acetylators (odds ratio = 1.01, 95% CI: 0.86, 1.22). The joint effects in the highest risk category (NAT2 slow acetylator, NAT1 fast acetylator, and current or ever cigarette smoking) as compared with the reference category (NAT2 fast acetylator, NAT1 slow acetylator, and never smoking) were associated with an odds ratio of 2.73 (95% CI: 1.70, 4.31). The importance of considering joint effects between genetic and environmental factors in the etiology of common complex diseases is underlined.     

Genetic variants on 15q25.1, smoking, and lung cancer: an assessment of mediation and interaction

Genome-wide association studies have identified variants on chromosome 15q25.1 that increase the risks of both lung cancer and nicotine dependence and associated smoking behavior. However, there remains debate as to whether the association with lung cancer is direct or is mediated by pathways related to smoking behavior. Here, the authors apply a novel method for mediation analysis, allowing for gene-environment interaction, to a lung cancer case-control study (1992-2004) conducted at Massachusetts General Hospital using 2 single nucleotide polymorphisms, rs8034191 and rs1051730, on 15q25.1. The results are validated using data from 3 other lung cancer studies. Tests for additive interaction (P = 2 × 10(-10) and P = 1 × 10(-9)) and multiplicative interaction (P = 0.01 and P = 0.01) were significant. Pooled analyses yielded a direct-effect odds ratio of 1.26 (95% confidence interval (CI): 1.19, 1.33; P = 2 × 10(-15)) for rs8034191 and an indirect-effect odds ratio of 1.01 (95% CI: 1.00, 1.01; P = 0.09); the proportion of increased risk mediated by smoking was 3.2%. For rs1051730, direct- and indirect-effect odds ratios were 1.26 (95% CI: 1.19, 1.33; P = 1 × 10(-15)) and 1.00 (95% CI: 0.99, 1.01; P = 0.22), respectively, with a proportion mediated of 2.3%. Adjustment for measurement error in smoking behavior allowing up to 75% measurement error increased the proportions mediated to 12.5% and 9.2%, respectively. These analyses indicate that the association of the variants with lung cancer operates primarily through other pathways.     

Cigarette smoking and colorectal cancer: APC mutations, hMLH1 expression, and GSTM1 and GSTT1 polymorphisms

The contribution of cigarette smoking to sporadic colorectal cancer may differ according to molecular aspects of the tumor or according to glutathione S-transferase M1 (GSTM1) or glutathione S-transferase T1 (GSTT1) genotype. In the prospective Netherlands Cohort Study on Diet and Cancer, adjusted incidence rate ratios for 1986-1993 were computed for overall colorectal cancer, tumors with and without adenomatous polyposis coli (APC) mutations, and tumors with and without human mut-L homologue 1 (hMLH1) expression, according to cigarette smoking characteristics (661 cases, 2,948 subcohort members). Case-only analyses were performed to estimate odds ratios for interaction between cigarette smoking and GSTM1 and GSTT1 genotypes. In comparison with never smokers, a high smoking frequency increased the risk of colorectal cancer (for a five-cigarette/day increment, incidence rate ratio (IRR) = 1.07, 95% confidence interval (CI): 1.03, 1.12), and this association was stronger in 371 tumors without a truncating APC mutation (IRR = 1.11, 95% CI: 1.05, 1.17). Long-term smoking was associated with lack of hMLH1 expression in 56 tumors (for a 10-year increment, IRR = 1.17, 95% CI: 1.00, 1.37). No statistically significant interactions between smoking and GSTM1 or GSTT1 genotype were observed. These results indicate that cigarette smoking is associated with risk of colorectal cancer, and this association may depend on molecular characteristics of the tumor as defined by APC mutation and hMLH1 expression status.     

细胞色素P450 2E1基因PstⅠ多态、腌制品与大肠癌关系的病例对照研究

目的：研究代谢酶细胞色素P450 2E1基因(CYP2E1)Pst Ⅰ多态性和腌制品与大肠癌易感性的关系。方法：采用人群基础的病例对照分子流行病学研究和PCR—RFLP技术,对126例大肠癌和343名健康对照Pst Ⅰ识别的CYP2E1基因型进行检测。结果：健康对照组CYP2E1基因野生型(C1／C1)为61．8％,杂合子(C1／C2)为35．8％,突变纯合子(C2／C2)为2．4％。调整年龄性别后,结肠癌病例中突变基因型频率54．9％(52．9％ C1／C2和2．0％ C2／C2)高于对照(OR 1．979,95％ CI 1．090—3．595),但直肠癌病例与对照比较,无统计学意义。分层分析发现,突变基因型、每周1或2次和隔天或每天吃腌制品单因素作用的大肠癌OR值分别1．935、2．122和2．315,而每周1或2次 突变型、隔天或每天吃 突变型联合作用后大肠癌OR值分别为2．272和3．127。分别分析结、直肠癌,腌制品对直肠癌的危险性在食用频率为每周1或2次时,差异有统计学意义,野生型和突变型的OR值分别为2．646和2．297,两者差异无统计学意义;而结肠癌危险性只有在Pst Ⅰ突变者隔天或每天吃腌制品时才剧增,OR值4．262(1．395～13．017),为野生型的2．69倍,差异有统计学意义。结论：CYP2E1 PstⅠG→C点突变是大肠癌的遗传易感性因素,与腌制品有协同作用,该作用在结肠癌尤为明显。     

Energy intake, body mass index, physical activity, and the colorectal adenoma-carcinoma sequence

Little is known about the precise relationship between energy intake, overweight, sedentary lifestyle, and steps in the colorectal adenoma-carcinoma pathway. We studied these parameters within a case-control study. Patients with adenomas < 10 mm (n = 154) or > 10 mm (n = 208) were compared with polyp-free controls (n = 426) for determining factors associated with adenoma formation, i.e., observed for small and large adenomas, or with adenoma growth only. Colorectal cancer cases (n = 171) were compared with population controls (n = 309) to determine factors specific to the final stage, cancer. Exercise reduced the risk of cancer [odds ratio (OR) = 0.3, 95% confidence interval (CI) = 0.2-0.5 for high vs. low physical activity] but had little influence on adenomas. High energy intake increased the risk of cancer [OR for 5th vs. 1st quintile (OR5) = 1.6, 95% CI = 0.9-2.9, p = 0.02], but not of adenomas. High body mass index (BMI) significantly increased the risk of large adenomas (OR5 = 2.1, 95% CI = 1.2-3.5, p = 0.02 and OR5 = 1.7, 95% CI = 1.0-3.1, p = 0.25) for large and small adenomas vs. polyp-free controls. Neither height nor weight nor BMI influenced the risk of cancer. Results were unmodified when controlling for dietary risk factors and family history. Energy intake, a sedentary lifestyle, and high BMI were independently associated with a high risk of cancer itself or large adenomas, which indicates an effect on promotion of colorectal tumors. These findings suggest that preventive advice regarding these factors should be provided, even late in life, to decrease the risk of colorectal cancer.     

A meta-analysis of the association of N-acetyltransferase 2 gene (NAT2) variants with breast cancer

The N-acetyltransferase 2 gene (NAT2) product is an enzyme important in carcinogen metabolism via activation and detoxification pathways. Therefore, NAT2 variants may represent underlying susceptibility to breast cancer. Because a number of studies of the association of NAT2 with breast cancer have been published, the authors performed a meta-analysis. They extracted all relevant data to examine evidence for a main effect (i.e., the effect in a model that does not include any interactions) of NAT2 phenotype and genotype on breast cancer risk. They summarized the evidence for modification by smoking and meat intake, sources of exposure to aromatic and heterocyclic amines, respectively, which are metabolized by NAT2. The authors identified seven studies that measured NAT2 phenotype and 20 studies that deduced phenotype via genotyping. They found no evidence for heterogeneity (Cochran's Q statistic p=0.74) and no statistically significant increased risk from NAT2 acetylation (slow/rapid) for breast cancer (summary odds ratio=1.02, 95% confidence interval: 0.95, 1.08). These results suggest that there is no overall association between the NAT2 slow- or rapid-acetylation phenotype and breast cancer risk. However, some evidence suggests that smoking may modify this association.     

Passive smoking, cytochrome P450 gene polymorphisms and dysmenorrhea

PURPOSE: This study investigated whether the association between passive smoking exposure and dysmenorrhea is modified by two susceptibility genes, CYP1A1MspI and CYP1A1HincII. METHODS: This report includes 1,645 (1,124 no dysmenorrhea, 521 dysmenorrhea) non-smoking and non-drinking newly wedding female workers at Anqing, China between June 1997 and June 2000. Multiple logistic regression models were used to estimate the associations of passive smoking exposure and genetic susceptibility with dysmenorrhea, adjusting for maternal age, BMI, age of menarche, education, vibration exposure, shift work, noise exposure, pregnancy history, perceived stress and physical laboring stress. RESULTS: In the passive smoking group, women who have C/C6235 genotype (OR = 1.8, 95% CI = 1.0-3.3) in CYP1A1MspI and Ile/Ile462 genotype (OR = 2.9, 95% CI = 1.1-7.7) in CYP1A1HincII was associated with an increased risk of dysmenorrhea. When stratified by women genotype, the adjusted OR of dysmenorrheal was 1.6 (95% CI = 1.2-2.1) for passive smoking group with Ile/Ile462 genotype, and 1.5 (95% CI = 1.0-2.1) with C/C6235 genotype, compared to non-passive smoking group, respectively. The data further showed that there was a significant combined effect between passive smoking and the CYP1A1 Msp1C/C6235 (OR = 1.5, 95% CI = 1.0-2.1), and HincII Ile/Ile462 (OR = 1.6, 95% CI = 1.2-2.1), respectively. CONCLUSION: CYP1A1 MspI and HincII genotypes modified the association between passive smoking and dysmenorrhea.     

Serum polychlorinated biphenyls, cytochrome P-450 1A1 polymorphisms, and risk of breast cancer in Connecticut women

Recent epidemiologic studies have suggested that genetic polymorphisms in the cytochrome P-450 1A1 gene (CYP1A1) may affect the relation between environmental exposure to polychlorinated biphenyls (PCBs) and breast cancer risk. The authors report results from a case-control study evaluating the potential effect of gene-environment interaction between CYP1A1 and serum PCB levels on breast cancer risk among Caucasian women in Connecticut. The study included 374 case women with histologically confirmed breast cancer and 406 noncancerous controls with information on both serum PCB level and CYP1A1 genotype (1999-2002). Compared with women who had the homozygous wild-type CYP1A1 m2 genotype, significantly increased risks of breast cancer were found for women with the CYP1A1 m2 variant genotype (odds ratio (OR) = 2.1, 95% confidence interval (CI): 1.1, 3.9), especially postmenopausal women (OR = 2.4, 95% CI: 1.1, 5.0). Risks associated with the CYP1A1 m2 variant genotype were highest for all women (OR = 3.6, 95% CI: 1.5, 8.2) and postmenopausal women (OR = 4.3, 95% CI: 1.6, 12.0) with higher serum PCB levels (611-2,600 ng/g). The CYP1A1 m1 and m4 genotypes were not associated with breast cancer risk independently or in combination with PCB exposure. In summary, the CYP1A1 m2 genetic polymorphism was associated with increased risk of female breast cancer and may modify the relation between PCB exposure and breast cancer risk.     

Molecular epidemiology and urothelial cancer

Tobacco smoking is the main cause of human urothelial cancer. It has been suggested that genetic susceptibility may contribute to the risk, because only a small portion of smokers develops urothelial cancer. Tobacco smoke contains many carcinogens which are activated or detoxified by phase-I or phase-II enzymes. The concentration of the ultimate carcinogen, which will react with DNA, is determined by the rate of activation and detoxification. Individuals with an increased rate of activation or a decreased rate of detoxification have a slightly higher level of bulky carcinogen-DNA adduct in the urothelial mucosa. Thus metabolic polymorphisms have been recognized as important determinants of carcinogen susceptibility, and recent efforts have shown that inter-individual differences in specific cytochrome P450 enzymes (CYPs), N-acetyltransferases (NAT), glutathione S-transferases (GST) and sulfotransferases (SULT) are often disproportionately represented in epidemiological studies between urothelial cancer cases and controls. It has been revealed that GSTM1 null genotype or NAT2 slow acetylator genotype may be associated with a small increase in urothelial cancer risk. Associations between other polymorphisms of metabolic enzymes and urothelial cancer are not well-known or are inconsistent. To reveal these associations, further well-designed and large-scale studies are needed.     

Maternal smoking and the risk of orofacial clefts: Susceptibility with NAT1 and NAT2 polymorphisms

BACKGROUND: Orofacial clefts are etiologically heterogeneous malformations. One probable cause is maternal smoking during pregnancy. The effect of maternal smoking may be modified by genes involved in biotransformation of toxic compounds derived from tobacco. We investigated whether polymorphic variants of fetal acetyl-N-transferases 1 (NAT1) and 2 (NAT2) interact with maternal cigarette smoking during early pregnancy to increase the risk of delivering an infant with an orofacial cleft. METHODS: In a California population-based case-control study, we genotyped 421 infants born with an isolated cleft and 299 nonmal-formed controls for 2 NAT1 and 3 NAT2 single nucleotide polymorphisms RESULTS: Although smoking was independently associated with increased risks for both isolated cleft lip +/- cleft palate and isolated cleft palate, no independent associations were found for NAT1 1088 or 1095 genotypes or for NAT2 acetylator status. However, the infant NAT1 1088 and 1095 polymorphisms were strongly associated with the risk of clefts among smoking mothers; infants with NAT1 1088 genotype AA versus TT (odds ratio [OR] = 3.9; 95% confidence interval = 1.1-17.2) and with NAT1 1095 genotype AA versus CC (OR = 4.2; 1.2-18.0). Infant NAT2 acetylator status did not appreciably affect susceptibility of the fetus to the teratogenic effects of maternal smoking. CONCLUSIONS: Our results suggest that maternal smoking during pregnancy may increase risk for orofacial clefts particularly among smokers whose fetuses have polymorphic variants of NAT1, an enzyme involved in phase II detoxification of tobacco smoke constituents.     

High Coffee Intake,but Not Caffeine,is Associated with Reduced Estrogen Receptor Negative and Postmenopausal Breast Cancer Risk with No Effect Modification by CYP1A2 Genotype

Associations between caffeine and coffee consumption and breast cancer risk are uncertain, with studies suggesting inverse and null associations. Variation in cytochrome P450 1A2 (CYP1A2), a gene responsible for caffeine metabolism, may modify these associations. Cases (n = 3,062) were recruited through the Ontario Cancer Registry and controls (n = 3,427) through random digit dialing. Logistic regression was used to evaluate associations between breast cancer risk and intakes of 7 caffeine-containing items and total caffeine, and examine whether a genetic variant in CYP1A2 (rs762551) modified these associations. Analyses were stratified by estrogen receptor (ER), menopausal, and smoking status. Generally, coffee and caffeine were not associated with breast cancer risk; however, a significant reduction in risk was observed with the highest category of coffee consumption [≥5 cups per day vs. never, multivariate-adjusted odds ratio (MVOR) = 0.71, 95% confidence interval (CI): 0.51, 0.98]. Variant rs762551 did not modify associations. In stratified analyses, high coffee intake was associated with reduced risk of ER- (MVOR = 0.41, 95% CI: 0.19, 0.92) and postmenopausal breast cancer (MVOR = 0.63, 95% CI: 0.43, 0.94). High coffee consumption, but not total caffeine, may be associated with reduced risk of ER- and postmenopausal breast cancers, independent of CYP1A2 genotype. Further studies are needed to replicate these findings.