Possible associations between antioxidant enzyme polymorphisms and metabolic abnormalities in patients with schizophrenia.

BACKGROUND: This study investigated the possible association between common and potentially functional polymorphisms of antioxidant enzymes and metabolic abnormalities in patients with schizophrenia. METHODS: The possible associations of the glutathione S-transferase (GST) M1 null and GSTT1 null genotypes, and the superoxide dismutase 2 (SOD2) Val16Ala polymorphism with the risks of being overweight and having metabolic syndrome were examined using a logistic regression analysis in 154 schizophrenic Japanese patients and 203 controls. RESULTS: Among smokers with schizophrenia, the risks of being overweight and having decreased high-density lipoprotein cholesterol were significantly higher in those with the GSTM1 null genotype than in those with the present genotype (odds ratio 3.20 and 3.15, P=0.03 and P=0.04, respectively), while among nonsmokers with schizophrenia, the risk of an abnormal waist circumference was lower in those with the GSTM1 null genotype (odds ratio 0.34, P=0.04). The risk of a decreased high-density lipoprotein cholesterol level was significantly higher in patients with the combined GSTM1 null and GSTT1 present genotypes than in those with the present genotypes of both genes (odds ratio 3.60, P<0.01). The SOD2 Val16Ala polymorphism was not associated with risk of metabolic abnormalities in either group. CONCLUSION: The present study suggests that the GSTM1 null genotype, in combination with smoking status or GSTT1 genotype, might be associated with the metabolic abnormalities in patients with schizophrenia.

Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease.

Glutathione S-transferases (GSTs) protect cells against exogenous and endogenous oxidative stress. GST polymorphisms are associated with the development of cardiovascular disease (CVD) and diabetes mellitus (DM), especially in current-smokers. Non-alcoholic fatty liver disease (NAFLD) is a predictor of future CVD or DM, because oxidative stress contributes to their pathogenesis. This study investigated whether the combination of smoking status and GST genotypes could affect the risk for NAFLD. A cross-sectional analysis was conducted among 713 Japanese participants (458 males and 255 females) during a health screening program. The GSTM1 null, GSTT1 null, GSTP1 A/B or B/B and GSTA1 A/B or B/B genotypes were determined and deemed to be high-risk genotypes. The prevalence of NAFLD was 18.7%. Among never-smokers, carriers of one, and those of two or more high-risk GSTM1, GSTP1 or GSTA1 genotypes were at a higher risk for NAFLD than those who were not carriers [odds ratio (95% confidence interval): 2.6 (1.1-5.9) and 3.3 (1.3-8.1), respectively], and the risk was further increased among current-smokers [4.6 (1.6-13.0) and 5.4 (1.2-23.7), respectively]. This is the first report to show that the combination of current-smoking and harboring high-risk GSTM1, GSTP1 and/or GSTA1 genotypes is interactively associated with the risk of NAFLD.

The combination of mitochondrial low enzyme-activity aldehyde dehydrogenase 2 allele and superoxide dismutase 2 genotypes increases the risk of hypertension in relation to alcohol consumption.

A cooperative role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) and superoxide dismutase 2 (SOD2) to maintain the vascular function has recently been demonstrated in nitrate tolerance. The present study examined whether the combination of low enzyme-activity variants of ALDH2 and SOD2 increases the risk of hypertension in relation to alcohol consumption. A total of 444 Japanese participants in a health-screening program were evaluated. The risk of hypertension among the individuals harboring both the ALDH2*2 allele and the SOD2 Val/Val genotype was significantly higher in drinkers than in nondrinkers (adjusted odds ratio, 6.22; 95% confidence interval, 2.26-17.1; P<0.001). Among these individuals, the systolic/diastolic blood pressure also increased by 0.24/0.14 mmHg for each 1g/day increase in alcohol consumption (P<0.001/P=0.003). These associations were observed, but the degree was lower among those with the other genotype combinations (0.11/0.10 mmHg; P=0.012/P=0.001). Information about the genetic predisposition to alcohol-related diseases may thus be useful to promote lifestyle modifications for high-risk individuals.

C-reactive protein levels, airflow obstruction, and chronic kidney disease.

OBJECTIVES: There is some evidence that chronic obstructive pulmonary disease and chronic kidney disease (CKD) may be related, perhaps through systemic inflammation, which is common to both. However, this relationship has not yet been clearly demonstrated. The aim of this study was to investigate the association between airflow obstruction, CKD, and C-reactive protein (CRP) levels in Japanese men. METHODS: The study included 11,587 men, aged 40-88 years, who underwent a health check-up. Airflow obstruction was defined as a forced expiratory volume in 1 s/forced vital capacity of <70%, and its severity was based on the Global Initiative for Chronic Obstructive Lung Disease guidelines (GOLD). CKD was defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m(2). RESULTS: Airflow obstruction was present in 7.9% of the participants, and 10.6% of the participants had CKD. The average CRP levels were 0.11 ± 0.36, 0.13 ± 0.41, and 0.18 ± 0.41 mg/L for subjects with normal lung function, GOLD stage I, and GOLD stage II-IV, respectively. With regard to CKD, the average CRP levels were 0.11 ± 0.32 and 0.18 ± 0.6 mg/L for subjects without and with CKD, respectively. Analysis of covariance showed no significant differences between the CRP level and lung function status or CKD after age was adjusted for. Logistic regression analysis showed no association among subjects with the three different lung function statuses after age, body mass index, hypertension, diabetes, hyper-low-density-lipoprotein-cholesterolemia, smoking, physical activity, and alcohol intake were controlled for. CONCLUSIONS: Based on the results of this study, we conclude that there is no interrelationship between CRP level, airflow obstruction, and CKD.

Association between frequency of drinking alcohol and chronic kidney disease in men.

OBJECTIVES: Chronic kidney disease (CKD) is a major public health problem. Epidemiological studies of the relationship between alcohol intake and CKD are scarce in Japan. This cross-sectional study aims to investigate the relationship between frequency of drinking alcohol and CKD in Japanese men. METHODS: The subjects were 9,196 men (mean ± standard deviation age, 57.9 ± 5.1 years) who underwent a health check-up. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2). Frequency of alcohol drinking was obtained from questionnaire and divided into five categories: nondrinkers, once or twice a week, three or four times a week, five or six times a week, and everyday drinkers. RESULTS: Multivariable-adjusted [age, body mass index, hypertension, diabetes, hyper-low-density lipoprotein (LDL) cholesterolemia, smoking, and physical activity] odds ratios and 95% confidence intervals (CIs) were calculated using logistic regression analysis. Compared with the results for the nondrinkers, the multivariable-adjusted odds ratios of CKD were as follows: 0.76 (95% CI 0.60-0.95) for 1-2 drinks per week, 0.74 (95% CI 0.59-0.93) for 3-4 drinks per week, 0.79 (95% CI 0.64-0.97) for 5-6 drinks per week, and 0.60 (95% CI 0.51-0.71) for everyday drinkers. There was a significant inverse trend across increasing frequency of drinking alcohol (p = 0.001 for trend). CONCLUSIONS: An inverse association was found between frequency of drinking alcohol and CKD in apparently healthy men.

Twelve-year cumulative incidence of airflow obstruction among Japanese males.

BACKGROUND: To date, there is very limited longitudinal data on COPD and incidence estimates in Japan. The aim of this study was to investigate the 12-year cumulative incidence of airflow obstruction (COPD) in Japanese males. METHODS: This study included 913 male subjects, aged 30-76 years, who underwent lung function tests at a medical check-up in 1994 (baseline), 1999, and 2006. The study group consisted of 263 persistent never smokers, 296 early quitters, 117 late quitters, and 237 persistent smokers without airflow obstruction at baseline. The 12-year cumulative incidence of airflow obstruction was estimated. The spirometric criteria for diagnosis of airflow obstruction were forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) of <0.7 and 5th percentile lower limit of normal (FEV(1)/FVC

Association between airflow obstruction and the metabolic syndrome or its components in Japanese men.

BACKGROUND: The aim of this cross-sectional study was to investigate the association between airflow obstruction and the metabolic syndrome (MS) or its components in Japanese men. METHODS: The study included 7,189 male subjects, aged 45-88 years, who underwent spirometric lung function tests at a medical check-up. The spirometric criteria for diagnosis of airflow obstruction were forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) <70%. The severity of airflow obstruction was defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline. RESULTS: The prevalence of airflow obstruction was 9.0% and the frequency of MS was 25.6%. In logistic regression models adjusting for age, body mass index, smoking, and alcohol, the risk of MS was higher in subjects with airflow obstruction of GOLD stage II-IV compared to those with normal lung function [odds radio (OR), 1.33; 95% confidence interval (95% CI), 1.01-1.76)]. Of the MS components, waist circumference (OR, 1.76; 95% CI, 1.24-2.50) and blood pressure (OR, 1.37; 95% CI, 1.08-1.74) were associated with airflow obstruction of GOLD stage II-IV, after controlling for potential confounders. CONCLUSION: Airflow obstruction of GOLD stage II-IV might be associated with MS, waist circumference and blood pressure components in Japanese men.

Correlation of C-reactive protein with disease severity in CT diagnosed emphysema.

BACKGROUND AND OBJECTIVE: Recent studies suggest that CRP levels are related to airflow obstruction. However, limited data exist on the relevance of CRP levels in individuals with or without emphysema. The aim of this study was to assess the relationship between the extent of emphysema, COPD severity and serum CRP levels. METHODS: Lung function tests and high-sensitivity CRP were examined in 651 males with stable disease who underwent CT screening for lung cancer. CRP levels were examined cross-sectionally in individuals with various degrees of emphysema and in those without emphysema. RESULTS: Emphysema was detected in 179 (34.7%) of 516 current smokers. Airflow obstruction was observed in 47 (28.8%) of 163 smokers with mild emphysema, in eight (57.1%) of 14 smokers with moderate emphysema, and in two of two individuals with severe emphysema. CRP levels were not higher in individuals with mild or moderate emphysema compared with individuals without emphysema. Among 98 individuals with airflow obstruction (19.0% of the 516 current smokers), there was a modest correlation between CRP levels and FEV(1)%. CONCLUSIONS: The severity of COPD varied in individuals with similar degrees of emphysema. CRP levels were not significantly higher in individuals with mild or moderate emphysema compared with individuals without emphysema but CRP levels were modestly correlated with FEV(1)% among individuals with airflow obstruction.

Association between combinations of glutathione-S-transferase M1, T1 and P1 genotypes and non-alcoholic fatty liver disease.

BACKGROUND/AIMS: Glutathione-S-transferases (GSTs) play a crucial role in antioxidant defence mechanisms, by detoxifying xenobiotics and by inactivating endogenous byproducts of oxidative stress. Functional failure, as a sequel of an altered GST genotype, may thus aggravate non-alcoholic fatty liver disease (NAFLD). This study investigated whether the GSTs genotypes could affect the risk for NAFLD. METHODS: A cross-sectional case-control analysis included 253 Japanese participants in a health screening programme. The GSTM1 null, GSTT1 null and GSTP1 Ile105Val variant genotypes were determined as putative high-risk genotypes. RESULTS: The incidence of NAFLD was 27.3%. The frequency of the GSTM1 null genotype was higher in NAFLD than in the control [adjusted odds ratio (OR), 2.00; 95% confidence intervals (CI), 1.01-3.95]. Moreover, any combination of two putative high-risk genotypes exhibited a higher risk for NAFLD with an adjusted OR from 3.52 (95% CI, 1.08-11.43)-4.01 (95% CI, 1.28-12.56). However, the significance for the combination of GSTM1 null and GSTT1 null genotypes only remained after Bonferroni's correction. In addition, the risk for NAFLD increased as the number of high-risk genotypes, and the OR among three high-risk genotypes carriers was 9.67 (95% CI: 1.61-58.26). CONCLUSION: This is the first report to show the impact of the GSTs genotypes on the development of NAFLD. This finding, which should be confirmed in further studies in larger populations, may help to develop a more targeted prevention programme at an early stage for subjects with an increased risk for NAFLD.

A preliminary investigation of the association between haptoglobin polymorphism, serum ferritin concentration and fatty liver disease.

BACKGROUND: The genetic polymorphism of haptoglobin (HP) has been associated with cardiovascular disease and type 2 diabetes. We hypothesized that the HP polymorphism could affect the incidence of nonalcoholic fatty liver disease (NAFLD). METHODS: This cross sectional case-control analysis included 337 Japanese participants in a health screening program. Fatty liver disease (FLD) was diagnosed by ultrasonography scanning and was classified into NAFLD based on the daily alcohol intake. The HP1 and HP2 alleles were determined using the PCR, and serum ferretin concentrations were measured. RESULTS: FLD and NAFLD were diagnosed in 91 and 69 subjects, respectively. The adjusted odd ratio (OR) of HP2 carriers vs. non-carriers was 11.8 [95% confidence intervals (CI), 1.3-104.0] for FLD, and 11.7 (95% CI, 1.3-107.9) for NAFLD. Male FLD cases with the HP2/HP2genotype had significantly higher ferretin concentrations than those without (P=0.003). The ferritin concentrations were correlated with the alanine-aminotransferase activities (r=0.48, P<0.001 in FLD cases with the HP2/HP2 genotype). Ferritin was an independent risk factor for FLD, and the incidence of FLD significantly increased in association with ferritin. CONCLUSIONS: This is a preliminary but the first report suggesting the HP2 allele to be a candidate risk factor for NAFLD.

Glutathione S-transferase A1 polymorphism as a risk factor for smoking-related type 2 diabetes among Japanese.

Glutathione S-transferases protect cells against exogenous and endogenous oxidative stress. Type 2 diabetes is associated with an increased production of reactive oxygen species and a reduction in antioxidant defenses. This study investigated whether GSTA1*A/*B and GSTP1Ile105Val polymorphisms could affect the risk for type 2 diabetes. A cross-sectional case-control analysis included 468 (326 men and 142 women) Japanese participants in a health screening program. The prevalence of type 2 diabetes was 11.3% (63 subjects: 52 male and 11 female). The frequency of GSTA1*B allele carriers was higher in diabetes than in non-diabetes, though the difference was not statistically significant (adjusted OR, 1.8; 95% CI, 0.9-3.4). The risk among the GSTA1*B allele carriers was significantly increased by current-smoking status (adjusted OR, 3.7; 95% CI, 1.1-12.7; vs. never-smoking non-carriers), whereas the smoking status was not an independent risk factor. The GSTP1 genotype alone or in combination with the smoking status did not affect the risk for diabetes. This is the first report to show that the GSTA1*B allele is a potential risk factor for smoking-related type 2 diabetes.

Association between glutathione S-transferase A1, M1 and T1 polymorphisms and hypertension.

The importance of oxidative stress in hypertension has recently received increasing attention. The association between the incidence of hypertension and a super family of antioxidant enzymes, glutathione S-transferase (GST)A1, GSTM1 and GSTT1, polymorphisms was investigated in 468 Japanese participants in a health screening program. The frequency of the GSTA1*B allele carriers was significantly higher in hypertensive patients than normotensive participants [adjusted odds ratio (OR): 1.8; 95% confidence interval (CI): 1.1-2.9]. The risk of hypertension was significantly increased in the GSTA1*B allele carriers having also the GSTM1 null genotype or both the GSTM1 and GSTT1 null genotypes (adjusted OR: 2.4; 95% CI: 1.2-4.9; adjusted OR: 3.1; 95% CI: 1.0-9.5, respectively). This is the first report identifying the GSTA1*B allele as a genetic risk factor for hypertension. The determination of the GST genotypes may help in identifying individuals at high-risk for hypertension.

Combined glutathione S-transferase T1 and M1 positive genotypes afford protection against type 2 diabetes in Japanese.

INTRODUCTION: Diabetes mellitus is associated with an increased production of reactive oxygen species and a reduction in antioxidant defenses. The aim of this study is to determine the association between the incidence of Type 2 diabetes and gene polymorphisms of glutathione S-transferase (GST), which modulates oxidative stress. MATERIALS & METHODS: The associations between the incidence of Type 2 diabetes and the GSTT1 and GSTM1 genotypes were analyzed in 469 Japanese participants in a health-screening program. RESULTS: The clinical characteristics and smoking status were obtained from the health screening record. The incidence of diabetes was 1.5-fold higher in the GSTT1 and GSTM1 null (-) genotype than the GSTT1 and GSTM1 present (+) genotype, respectively. Although the effect of each null genotype was not significant, the combined GSTT1+/GSTM1+ genotypes conferred a significant reduction in risk of diabetes in comparison with the other combinations of genotypes (adjusted odds ratio [OR]: 0.30; 95% confidence interval [CI]: 0.12-0.71). In stratified analyses by smoking status, the incidence of diabetes was significantly higher in never-smokers with the GSTT1- genotype than those with the GSTT1+ genotype (OR: 2.85; 95% CI: 1.17-6.94) and increased significantly in current smokers (OR: 5.91; 95% CI: 1.96-17.88). The effect of the GSTM1- genotype was significant only in current smokers. CONCLUSION: This study demonstrated that the GSTT1- and GSTT1-/GSTM1- genotypes are independent risk factors for development of Type 2 diabetes regardless of the smoking status of the patient, and that these genotypes and current smoking were interactively associated with the incidence of Type 2 diabetes.

Prevalence of airflow limitation on medical check-up in Japanese subjects.

The prevalence and mortality of chronic obstructive pulmonary disease (COPD) is expected to increase in the future throughout the world. Little data is available on the prevalence of airflow limitation in Japan, especially on medical check-up. The purpose of this study was to assess the prevalence of airflow limitation in Japanese subjects during medical check-ups. The study subjects were 13,534 Japanese subjects (8,583 males and 4,951 females) aged 40-69 years who underwent medical check-ups at the Japanese Red Cross Kumamoto Health Care Center. Pulmonary function data were analyzed according to smoking habits in each age group. The spirometric criteria for diagnosis of airflow limitation were forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 70%. The severity of COPD was defined according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. People with a medical diagnosis of asthma or individuals who had other pulmonary diseases were excluded from a diagnosis of COPD. The prevalence of airflow limitation was 7.0% in all subjects, 9.1% in males and 3.3% in females. Using the GOLD system, the prevalence of mild, moderate, severe and very severe airflow limitation was 7.06, 1.92, 0.10 and 0.00%, respectively, in males. In females, the prevalence of mild, moderate, severe and very severe airflow limitation was 2.67, 0.63, 0.02 and 0.00%, respectively. Only 10 cases with airflow limitation reported a previous diagnosis of COPD. These results suggest that screening spirometry during medical check-ups can identify many COPD patients not aware of this disease and highlight the need for enhanced screening efforts, intervention and treatment.

Case report of intralobar pulmonary sequestration detected by lung cancer screening with low-dose spiral CT.

A 52-year-old man underwent lung cancer screening with low-dose spiral computed tomography (CT) in a medical check-up at the Japanese Red Cross Kumamoto Health Care Center. He was asymptomatic. Chest x-ray on a medical check-up showed no abnormal shadows. CT scans revealed a nodule in the right lower lung, suggestive of its connection to the descending thoracic aorta. A diagnosis of pulmonary sequestration was considered. He was transferred to Kumamoto University Hospital for further examination. Contrast enhanced multidetector CT images demonstrated that a nodule in the right lower lobe and an anomalous artery ran from the descending thoracic aorta, flowed through the right lower lobe and returned to the right inferior pulmonary vein. Intralobar pulmonary sequestration was confirmed by contrast enhanced multidetector CT. We report this case of asymptomatic intralobar pulmonary sequestration diagnosed using contrast enhanced multidetector CT.

Impact of CYP2D6*10 on H1-antihistamine-induced hypersomnia.

OBJECTIVE: This study investigated the relevance of the cytochrome P450 (CYP) 2D6 genotype to the adverse drug reactions (ADRs) of H1-antihistamines and the level of sedation. METHODS: Japanese participants in a health screening program were asked to describe any past history of ADRs. Any subjects reporting ADRs induced by H1-antihistamines were then individually interviewed and defined as cases. Excessive daytime sleepiness, which had occurred in the cases as an H1-antihistamine-induced ADR, was assessed by the Epworth sleepiness scale (ESS), and an ESS score >or=12 was considered hypersomnia. CYP2D6*4, *5, *14, and *10 were genotyped by a panel of polymerase chain reaction techniques. RESULTS: Out of 2,074 participants, 100 cases (M:F = 37:63, mean age 51.9 +/- 9.2 years) were eligible for analysis. The most common etiological drug was chlorpheniramine, which is the most frequently used H1-antihistamine in Japan. CYP2D6*10 allele and genotypes were more frequently found in the cases than in the healthy Japanese population in a large study (P < 0.005 and P = 0.039, respectively), but no difference was observed in the null alleles and genotypes. The ESS scores in 75 cases (M:F=25:50) who had experienced excessive daytime sleepiness were 9.5 +/- 5.5 in men and 12.9 +/- 6.1 in women (P < 0.001, cases vs. 34 subjects without symptoms; P = 0.001 men vs. women). The occurrence of hypersomnia increased as the number of CYP2D6 mutant alleles increased (P = 0.045). CONCLUSION: The results suggest that the presence of the CYP2D6*10 allele is a risk factor for development of H1-antihistamine-induced ADRs in Japanese.

Emphysema detected by lung cancer screening with low-dose spiral CT: prevalence, and correlation with smoking habits and pulmonary function in Japanese male subjects.

OBJECTIVE: Screening with low-dose spiral CT is a promising new tool for early lung cancer detection. A study was undertaken to assess the prevalence of emphysema detected by CT screening, and to assess the correlation between the extent of emphysema and the severity defined according to the recently published Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. METHODS: After informed consent, CT screening and pulmonary function tests were performed on 615 men between the ages of 40 and 69. Severity of emphysema was assessed visually. Only the pulmonary function data for male subjects were analysed because there were too few female subjects with emphysema. RESULTS: Emphysema was detected in 30.5% of current smokers, 14.1% of former smokers and 3.0% of non-smokers. In male current smokers, airflow obstruction (FEV(1)/FVC < 0.7) was seen in 18.1% of subjects with mild emphysema, and in 33.3% of subjects with moderate emphysema. FEV(1) values were less than 80% of the predicted normal in 8.5% of subjects with mild emphysema, and 28.6% of subjects with moderate emphysema. The percentage of male subjects with emphysema equivalent to GOLD stage 0 was 90.0% for subjects in their 40s, 82.5% for those in their 50s, and 68.2% for those in their 60s. CONCLUSION: A considerable percentage of the subjects with emphysema as detected by CT screening had GOLD stage 0. CT screening assists in detecting early-stage emphysema.

Phenotype-genotype analysis of CYP1A2 in Japanese patients receiving oral theophylline therapy.

OBJECTIVE: To clarify the association between the cytochrome P450 (CYP) 1A2 genotype with the CYP1A2 phenotype and to search for the CYP1A2*1K haplotype, which has been shown to decrease CYP1A2 inducibility and/or other functional polymorphisms in Japanese. METHODS: Two polymorphisms, CYP1A2*1C and CYP1A2*1F, were genotyped in 126 patients receiving oral slow-release theophylline (TP) therapy and in 224 healthy volunteers. The CYP1A2 phenotype was assessed by the plasma [1-methyluric acid (1U)+3-methylxanthine (3X)]/TP ratio in the patients. The volunteers were given 150 mg caffeine, and the urine [1X+1U+5-acetylamino-6-amino-3-methyluracil (AAMU)]/17U ratio was used for CYP1A2 phenotyping. CYP1A2 intron 1 and six exons (exon 2-exon 7) were sequenced in the patients whose (1U+3X)/TP ratios were below the mean-2SD of those of all patients, and intron 1 was also sequenced in an additional 20 healthy volunteers exhibiting putative low CYP1A2 activities. RESULTS: The individual (1U+3X)/TP ratios ranged from 0.007 to 0.21 (a 30-fold difference) in the patients, and the (1X+1U+AAMU)/17U ratios ranged from 1.6 to 112 (a 70-fold difference) in the healthy volunteers. The CYP1A2 activities were not significantly influenced by CYP1A2*1C or CYP1A2*1F. We found no functional polymorphisms by a sequencing analysis. CONCLUSION: These results suggest that the CYP1A2*1C and CYP1A2*1F genotypes are not crucial factors for the variability of CYP1A2 activity and that the CYP1A2*1K haplotype is either nil or only shows a very low frequency in Japanese.