Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population.

OBJECTIVES: Exposure to reactive oxygen species (ROS) through cigarette smoking is thought to contribute to the development of systemic lupus erythematosus (SLE). Metabolic enzymes are involved in ROS production. The aim of this study was to evaluate the modifying effect of metabolic polymorphisms on the association of cigarette smoking with SLE risk in a Japanese population. METHODS: We investigated the relationship of the cytochrome P450 (CYP) 1A1 rs4646903 and glutathione S-transferase (GST) M1 deletion polymorphisms to SLE risk with attention to interaction with cigarette smoking among 151 SLE cases and 421 controls in female Japanese subjects. Unconditional logistic regression was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for several covariates. RESULTS: Smokers with the CC genotype of CYP1A1 rs4646903 were significantly associated with increased risk of SLE (OR 9.72, 95% CI 2.73-34.6). Similarly, smokers with the combined CYP1A1 rs4646903/GSTM1 'at-risk' genotype were significantly associated with increased risk of SLE (OR 17.5, 95% CI 3.20-95.9). More than 60% of the excess risk for SLE in smokers with the CC genotype and smokers with the combined 'at-risk' genotype was due to an additive interaction. A lack of association of the GSTM1 genotypes with smoking was observed. CONCLUSIONS: Our results suggest that a combination of smoking and either the CYP1A1 rs4646903 genotype or the combined metabolic genotype plays an important role in SLE susceptibility in our Japanese population. Additional studies are warranted to confirm the metabolic polymorphism-smoking interaction suggested in the present study.

Dietary patterns and risk of Parkinson's disease: a case-control study in Japan.

BACKGROUND: Nearly all epidemiologic studies examining the association between the risk of Parkinson's disease (PD) and diet have focused on single foods and specific nutrients. However, epidemiologic evidence for the association of dietary pattern with PD, namely the measurement of overall diet by considering the cumulative effects of nutrients is extremely limited. We conducted a hospital-based case-control study in Japan to examine the relationship between dietary patterns and the risk of PD. METHODS: Patients with PD diagnosed using the UK PD Society Brain Bank criteria (n = 249) and controls without neurodegenerative diseases (n = 368) were recruited. At the time of recruitment, dietary intake during the preceding 1 month was assessed using a validated, self-administered diet history questionnaire. Dietary patterns from 33 predefined food groups (energy-adjusted food g/day) were extracted by factor analysis. RESULTS: Three dietary patterns were identified: 'Healthy', 'Western' and 'Light meal' patterns. After adjustment for potential non-dietary confounding factors, the Healthy pattern, characterized by a high intake of vegetables, seaweed, pulses, mushrooms, fruits and fish, was inversely associated with the risk of PD with a border-line significance (P for trend = 0.06). Multivariate Odds ratio (95% confidence intervals) for PD in the highest quartile of the Healthy pattern was 0.54 (0.32-0.92) compared with the lowest quartile. No associations with PD were detected for the other two dietary patterns. CONCLUSION: In this case-control study in Japan, a dietary pattern consisting of high intakes of vegetables, fruits and fish may be associated with a decreased risk of PD.

Lack of association of dairy food, calcium, and vitamin D intake with the risk of Parkinson's disease: a case-control study in Japan.

Three previous cohort studies in the USA reported that dairy product consumption was significantly associated with an increased risk of Parkinson's disease (PD) in men, but not in women. We examined the relationship between consumption of dairy products, calcium, and vitamin D and the risk of PD using data from a multicenter hospital-based case-control study in Japan. Included were 249 cases within 6 years of onset of PD based on the UK PD Society Brain Bank clinical diagnostic criteria. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, body mass index, and dietary factors including cholesterol, dietary glycemic index, vitamin E, ß-carotene, vitamin B(6), caffeine, iron, and alcohol. Total dairy product consumption was not materially associated with the risk of PD (P for trend = 0.62). No evident relationships were observed between intake of milk, yogurt, cheese, or ice cream and the risk of PD (P for trend = 0.75, 0.63, 0.59, and 0.35, respectively). There were no measurable associations between consumption of calcium or vitamin D and PD (P for trend = 0.37 and 0.69, respectively). No significant interactions were observed between the dietary exposures and sex regarding PD. Our results suggest that intake of dairy products, calcium, and vitamin D was not related to PD, regardless of sex. However, such null relationships might be a consequence of PD.

Dietary intake of antioxidant vitamins and risk of Parkinson's disease: a case-control study in Japan.

BACKGROUND: antioxidant vitamins are expected to protect cells from oxidative damage by neutralizing the effects of reactive oxygen species. However, epidemiological evidence regarding the associations between antioxidant vitamin intake and Parkinson's disease (PD) is limited and inconsistent. We investigated the relationship between dietary intake of selected antioxidant vitamins, vegetables and fruit and the risk of PD in Japan using data from a multicenter hospital-based case-control study. METHODS: included were 249 patients within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Information on dietary factors was collected using a validated self-administered diet history questionnaire. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, body mass index, dietary intake of cholesterol, alcohol, total dairy products, and coffee and the dietary glycemic index. RESULTS: higher consumption of vitamin E and ß-carotene was significantly associated with a reduced risk of PD after adjustment for confounders under study: the adjusted odds ratio in the highest quartile was 0.45 (95% confidence interval [CI]: 0.25-0.79, P for trend = 0.009) for vitamin E and 0.56 (95% CI: 0.33-0.97, P for trend = 0.03) for ß-carotene. Stratified by sex, such inverse associations were significant only in women. No material relationships were shown between intake of vitamin C, α-carotene, cryptoxanthin, green and yellow vegetables, other vegetables, or fruit and the risk of PD. CONCLUSIONS: higher intake of vitamin E and ß-carotene may be associated with a decreased risk of PD.

GST polymorphisms, interaction with smoking and pesticide use, and risk for Parkinson's disease in a Japanese population.

Patients with idiopathic Parkinson's disease (PD) appear to have reduced capacity for detoxification of certain environmental compounds. The glutathione S-transferases (GSTs) are candidate genes for PD because they are involved in the metabolism of pesticides and cigarette smoke. We investigated the relationship of the seven GST polymorphisms (GSTM1 deletion, GSTT1 deletion, GSTP1 rs1695, GSTO1 rs4925, GSTO1 rs11191972, GSTO2 rs156697 and GSTO2 rs2297235) and PD risk with special reference to the interaction with pesticide use or cigarette smoking among 238 patients with PD cases and 370 controls in a Japanese population. None of the GST polymorphisms were associated with PD. GSTO1 rs4925 and GSTO2 rs2297235 were found to be in strong linkage disequilibrium (D' = 0.98). Cigarette smoking was significantly associated with decreased risk of PD. However, no interaction of smoking with any of the GST polymorphisms was observed. Self-reported pesticide use was not associated with increased risk of PD. There was no evidence of interaction between self-reported pesticide use and either GST polymorphism. Our results suggest that the tested GST polymorphisms did not play an important role in PD susceptibility in our Japanese population. Our study does not give evidence of interaction between the GST polymorphisms and smoking may although this study provided sufficient statistical power to detect modest interaction. As for interaction between GSTP polymorphisms and pesticide use, the power of this study to detect an interactive effect was low due to a small number of pesticide users. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the GST polymorphisms in PD development.

Active and passive smoking and risk of Parkinson's disease.

OBJECTIVE: To assess the association between active and passive smoking and the risk of Parkinson's disease (PD), a case-control study with 249 PD patients and 369 controls was carried out in Japan. METHODS: Information on smoking was obtained through a self-administered questionnaire. Adjustment was made for age, sex, region of residence, educational level, and occupational exposure. RESULTS: Ever having smoked cigarettes was associated with a reduced risk of PD [adjusted odds ratio = 0.38; 95% confidence interval (CI): 0.24-0.59]. Risk for former smokers was intermediate between the high risk for never smokers and the low risk for current smokers. Adjusted odds ratios for former and current smokers were 0.51 (95% CI: 0.32-0.82) and 0.12 (95% CI: 0.05-0.26), respectively. There was an inverse dose-response gradient with pack-years smoked. No significant association was detected for passive smoking exposure. CONCLUSION: Our results appear to confirm data from previous epidemiological studies.

Metal ion and vitamin adsorption profiles of phosphate binder ion-exchange resins.

AIMS: To determine the metal ion and vitamin in vitro adsorption profile of sevelamer hydrochloride (sevelamer-HCl) and colestilan(INN)/colestimide(JAN), a novel ion-exchange resin being developed as a phosphate binder for end-stage renal disease (ESRD) patients undergoing hemodialysis, adsorption of metal ions (iron, cobalt, copper and zinc) and vitamins (B6, B12, C, K and folic acid) essential for hematopoiesis/blood coagulation was assessed. METHODS: Mixtures of each resin (colestilan or sevelamer-HCl, 4 mg/ml) and metal ions (Fe(III), Fe(II), Co(II), Cu(II), and Zn(II), 1 microg/ml) were adjusted to pH 1.2 or 6.8 and incubated at 37 degrees C for 1 hour. Metal ions in the recovered filtrate were detected by inductively coupled plasma optical emission spectrometry. In addition, the mixtures of each resin (4 mg/ml) and vitamins (B6, B12, C, K and folic acid, 0.5 - 250 microg/ml) were adjusted to pH 6.8 and incubated at 37 degrees C for 0.5 hour. The vitamin concentrations in the recovered filtrate were quantified by HPLC. RESULTS: Colestilan did not adsorb any metals tested at either pH level, whereas sevelamer-HCl adsorbed copper(II) and zinc(II) ion at pH 6.8 with adsorption ratios of 99% and 38%, respectively. Both resins showed almost complete adsorption of vitamin C, vitamin K, and folic acid, but weak adsorption of vitamin B6, and no adsorption of vitamin B12. CONCLUSIONS: The differing adsorption profiles for metal ions and vitamins between sevelamer-HCl and colestilan may be of importance for the individualized management of anemia and malnutrition in chronic hemodialysis patients receiving phosphate binding ion-exchange resins for the control of hyperphosphatemia.

Cigarette smoking, N-acetyltransferase 2 polymorphisms and systemic lupus erythematosus in a Japanese population.

Cigarette smoking may be associated with an increased risk of systemic lupus erythematosus (SLE), but the underlying mechanism of this association remains unclear. N-acetyltransferase 2 (NAT2) is highly variable and detoxifies aromatic amines, an important class of carcinogens in tobacco smoke. Individuals who possess homozygous polymorphic alleles have a slower rate of metabolic detoxification of aromatic amines. We investigated the relationship of the NAT2 polymorphism to the risk of SLE with special reference to the interaction with cigarette smoking among 152 SLE cases and 427 controls in a female Japanese population. NAT2 4, NAT2 5B, NAT2 6A and NAT2 7B alleles were detected with polymerase chain reaction-restriction fragment length polymorphism. Individuals carrying the 4/4 genotype are rapid acetylators, whereas those with homozygous non- 4 genotypes have a slow acetylator phenotype. Cigarette smoking was associated with an increased risk of SLE (odds ratio [OR] = 2.26; 95% confidence interval [CI] = 1.46-3.50). The slow acetylator genotype of NAT2 was significantly associated with an increased risk of SLE (OR = 2.34, 95% CI = 1.21-4.52) compared with the rapid acetylator genotype. A gene-environment interaction was suggested, with a combination of the NAT2 slow acetylator genotype and smoking conferring significantly higher risk (OR = 6.44, 95% CI = 3.07-13.52; attributable proportion due to interaction = 0.50, 95% CI = 0.12-0.88), compared with the NAT2 rapid acetylator genotype and no history of smoking. This study suggests that, in this Japanese population, the NAT2 slow acetylator status may be a determinant in susceptibility to SLE.

A dose-escalation study of rituximab for treatment of systemic lupus erythematosus and Evans' syndrome: immunological analysis of B cells, T cells and cytokines.

OBJECTIVE: Accumulating evidence suggests that B-cell depletion therapy by rituximab may be effective for autoimmune disorders. However, an optimal dose of rituximab and a mechanism of its action remain to be established. We performed a dose-escalation study for treatment of Japanese patients with autoimmune diseases including eight with SLE and one with Evans' syndrome. METHODS: Rituximab was infused intravenously, weekly 4 times in a dose-escalating fashion at three different doses of 100, 250 or 375 mg/m(2) to three patients each. Immunological parameters were monitored at certain points until 12 months after the treatment. RESULTS: Rituximab was well tolerated and safe in these patients. Seven out of eight SLE patients and one with Evans' syndrome clinically responded completely or partially to the treatment. Four patients achieved long-term remission (18-30 months) without any additional treatment. In these patients, a significant decrease in circulating B cells continued for 6 months after the treatment. The mean fluorescence intensities of CD19, CD21, CD40 and BR3 on the residual B cells as well as the percentage of CD69+ CD4+ T cells decreased significantly. Serum TNF-alpha levels decreased significantly on day 2. The Th1/Th2 balance of CD4+ T cells gradually shifted towards a Th1 type by 6 months. CONCLUSION: In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.

Breastfeeding and the risk of wheeze and asthma in Japanese infants: the Osaka Maternal and Child Health Study.

Epidemiological evidence for an effect of breastfeeding on asthma continues to be inconclusive. The present prospective study examined the relationship between breastfeeding and the risk of wheeze and asthma in Japanese infants. A birth cohort of 763 infants was followed. The first survey during pregnancy and the second survey between 2 and 9 months postpartum collected information on potential confounding factors. Data on breastfeeding, wheeze, and asthma were obtained from questionnaires in the third survey from 16 to 24 months postpartum. Adjustment was made for maternal age, maternal and paternal history of asthma, atopic eczema, and allergic rhinitis, indoor domestic pets (cats, dogs, birds, or hamsters), family income, maternal and paternal education, maternal smoking during pregnancy, baby's sex, baby's older siblings, household smoking in the same room as the infant, and time of delivery before the third survey. By the third survey, the cumulative incidence of wheeze and asthma was 22.1% and 4.3%, respectively. Neither exclusive breastfeeding for 4 months or more nor partial breastfeeding for 6 months or more were materially related to the risk of wheeze. No measurable association was observed between exclusive breastfeeding for 4 months or more and the risk of asthma. Partial breastfeeding for 6 months or more was inversely related to the risk of asthma although the adjusted odds ratio (OR) was not statistically significant. When infants were stratified according to whether there was a negative or positive allergic history in at least 1 parent, a nearly 40% and 60% decrease, respectively, in the ORs were found for exclusive and partial breastfeeding only in infants without a parental allergic history, although the ORs were not statistically significant. The present prospective study showed no statistically significant relationship between breastfeeding duration and the risk of wheeze or asthma in Japanese infants.

Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus.

OBJECTIVE: Identification of the genes responsible for systemic lupus erythematosus (SLE). METHODS: All the exons and putative promoter regions of 53 candidate genes (TNFRSF6/Fas, TNFSF6/FasL, Fli1, TNFSF10/TRAIL, TNFSF12/TWEAK, Bcl-2, PTEN, FADD, TRADD, CDKN1A, TNFRSF1A/TNFR1, TNFRSF4/OX40, TNFSF4/OX40L, TNFSF5/CD40L, TNFSF13B/BAFF, ICOS, CTLA4, CD28, FYN, G2A, CR2, PTPRC/CD45, CD22, CD19, Lyn, PDCD1, PTPN6, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, TGFBR3, CD3Z, DNASE1, APCS, MERTK, C3, C1QA, C1QB, C1QG, C2, MBL2, IGHM, IL-2, IL-4, IL-10, IFNG, TNFA, MAN2A1, TNFRSF11A/RANK, TNFRSF11B/OPG, TNFSF11/OPGL) were screened for single nucleotide polymorphisms (SNPs) and their association with SLE was assessed by case-control studies. A total of 509 cases and 964 controls of Japanese descent were enrolled. RESULTS: A total of 316 SNPs was identified. When analysed in the Japanese population, the allele frequencies of T at rs7951 and G at rs2230201 of the C3 gene were 0.110 and 0.626, respectively, in SLE patients; significantly higher than the frequencies of 0.081 and 0.584, respectively, in controls [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.05-1.86, P = 0.016 and OR=1.19, 95% CI = 1.01-1.41, P = 0.038, respectively]. The mean serum C3 level of carriers of the rs7951 T allele was significantly lower than that of non-carriers of the T allele in 87 SLE patients whose medical records were available (P = 0.0018). CONCLUSION: rs7951 T allele of the C3 gene was significantly associated with SLE, and decreased serum level of C3 seems to be correlated with this allele.

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Genetic polymorphisms of cytochrome P450 1A1 and risk of gallbladder cancer.

The relation between cytochrome P4501A1 (CYP1A1) gene polymorphisms and the risk of gallbladder cancer was examined. To clarify individual differences in susceptibility to gallbladder carcinogenesis, we investigated the frequency of the Mspl and Ile-Val polymorphisms of the CYP1A1 gene, in 52 patients with gallbladder cancer (32 females, 20 males) and 104 healthy controls (64 females, 40 males). We then examined the relationship between the CYP1A1 polymorphisms and the development of gallbladder cancer in members of both sexes. A statistical difference in the frequencies of the MspI and Ile-Val polymorphisms or their alleles (ml, m2 and Ile, Val) was not observed in the male patients and controls. Among females, however, the frequencies of genotypes C and Ile/Val were significantly higher (p < 0.05) in the patients than in their controls. Moreover, the frequency of the hetero genotype Ile/Val was statistically higher (p < 0.05) in the female patients than in the male patients. This study demonstrated a significant over-representation of genotypes C and Ile/Val in female patients with gallbladder cancer. Females with genotypes C and/or Ile/Val may have a high genetic susceptibility to the development of gallbladder cancer.

Metabolic gene polymorphism frequencies in control populations.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

Apolipoprotein E genotype, serum lipids, and colorectal adenomas in Japanese men.

We examined the relation of serum lipids and apolipoprotein E genotype to colorectal adenomas among 205 cases and 220 controls with normal colonoscopy in Japanese men. With adjustment for body mass index, cigarette smoking, alcohol use, and other covaiates, odds ratios of proximal and distal adenomas associated with the presence of an allele varepsilon4 were 0.59 (95% confidence interval 0.23-1.45) and 0.99 (0.50-1.98), respectively. While serum total and LDL cholesterol were unrelated to both proximal and distal adenomas, serum triglycerides were positively related to distal adenomas. The findings suggest that altered lipid metabolism may be differentially associated with tumorigenesis in the proximal and distal colorectum.

Glutathione S-transferase polymorphisms and risk of colorectal adenomas.

Glutathione S-transferases (GSTs) are a superfamily of detoxification enzymes that may play an important role in human carcinogenesis. While the genetic polymorphisms GSTM1 and GSTT1 have drawn particular interest in relation to cancer susceptibility, previous studies of colorectal cancer are inconsistent regarding their role. We examined the relation between GSTM1 and GSTT1 genotypes combined and colorectal adenomas, and the interaction with cigarette smoking among 205 cases of colorectal adenomas and 220 controls with normal total colonoscopy in Japanese men. Neither GSTM1 nor GSTT1 was related to colorectal adenomas, nor were the null genotypes of GSTM1 and GSTT1 combined. The lack of an association with GSTM1 and GSTT1 genotypes combined persisted even when the analysis was done separately for proximal and distal colorectal adenomas. A three- to fivefold significant increase in the odds of colorectal adenomas was observed among men with a high exposure to cigarette smoking across the genotype groups, and a statistically significant increasing trend was noted within each genotype group. The present findings do not support the role for GSTM1 and GSTT1 genotypes in the development of colorectal adenomas.

Recognition of the deleterious effects of smoking among senior high school male students.

The purpose of this study was to evaluate the prevalence of, attitudes towards, and knowledge about cigarette smoking among senior high school male students with different levels of academic ability. Self-administered anonymous questionnaires were distributed to 2014 students in July 2001. The prevalence of current smokers was 10.9% overall. The percentage of nonsmokers increased with academic ability level in both first and second graders. Students who recognize that cigarette smoking is associated with various diseases were more numerous than those reported in a nationwide Japan survey. Their recognition regarding the deleterious effects of smoking inclined toward diseases of the respiratory system. Correct knowledge concerning the detrimental effects of smoking on 10 selected diseases differed according to academic ability levels. They also thought that environmental tobacco smoke exposure was harmful to nonsmokers' health (86.6%). Although they fully understood the harmful effects of smoking, the percentage of current smokers who wanted to quit smoking (24.7%) was somewhat lower than that of those who did not (30.1%). A considerable number of current smokers, 95 of 219, had not made up their mind to quit smoking. To reduce the numbers of adult smokers, it is important not only to prevent students from starting to smoke or to encourage smokers to quit but also to guide undecided smokers in how to quit.

Lymphocyte DNA adducts and polymorphism in the DNA repair enzyme XPD.

The effect of genetic polymorphism of DNA repair enzyme on the DNA adduct levels was evaluated in this study. We explored the relationship between polymorphism in the nucleotide excision repair enzyme XPD and DNA adduct levels in lymphocytes. Lymphocyte DNA adducts were measured by a (32.)

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.

[Lung cancer risk and genetic polymorphism at the glutathione S-transferase P1 locus in male Japanese].

The glutathione S-transferases (GSTs) are widely expressed in mammalian tissues and involved in Phase II detoxification reactions. The GSTs form a supergene family consisting of four distinct families, named alpha (GSTA), mu (GSTM) theta (GSTT) and pi (GSTP). Several of the GST genes are polymorphic in humans and are currently being investigated as possible cancer-risk modifiers. Among the GST genes, we examined GSTP1 polymorphism in exon 5 among male lung cancer patients (n = 86, male Japanese) and male healthy controls (n = 80, male Japanese) by restriction fragment length polymorphism-polymerase chain reaction method. The cancer patients showed frequency of the GSTP1 mutated genotype (individuals having at least one mutant allele, 29.1%) very similar to that of the control subjects (28.8%). After adjusting for smoking status, no association was found between the GSTP1 mutated genotype and lung cancer risk (odds ratio: 0.95; 95% confidence interval: 0.48-1.90). When study subjects were divided into two subgroups based on smoking status, the GSTP1 mutated genotype was not associated with an increased risk of lung cancer among smokers and non-smokers. These results suggest that GSTP1 polymorphism in exon 5 alone may not increase the risk of lung cancer in male Japanese.