Multi-ancestry genome-wide analysis identifies shared genetic effects and common genetic variants for self-reported sleep duration.

Both short (≤6 h per night) and long sleep duration (≥9 h per night) are associated with increased risk of chronic diseases. Despite evidence linking habitual sleep duration and risk of disease, the genetic determinants of sleep duration in the general population are poorly understood, especially outside of European (EUR) populations. Here, we report that a polygenic score of 78 European ancestry sleep duration single-nucleotide polymorphisms (SNPs) is associated with sleep duration in an African (n = 7288; P = 0.003), an East Asian (n = 13 618; P = 6 × 10-4) and a South Asian (n = 7485; P = 0.025) genetic ancestry cohort, but not in a Hispanic/Latino cohort (n = 8726; P = 0.71). Furthermore, in a pan-ancestry (N = 483 235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 73 loci are associated with genome-wide statistical significance. Follow-up of five loci (near HACD2, COG5, PRR12, SH3RF1 and KCNQ5) identified expression-quantitative trait loci for PRR12 and COG5 in brain tissues and pleiotropic associations with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.

Evidence-based cancer prevention recommendations for Japanese.

A comprehensive evidence-based cancer prevention recommendation for Japanese was developed. We evaluated the magnitude of the associations of lifestyle factors and infection with cancer through a systematic review of the literature, meta-analysis of published data, and pooled analysis of cohort studies in Japan. Then, we judged the strength of evidence based on the consistency of the associations between exposure and cancer and biological plausibility. Important factors were extracted and summarized as an evidence-based, current cancer prevention recommendation: 'Cancer Prevention Recommendation for Japanese'. The recommendation addresses six important domains related to exposure and cancer, including smoking, alcohol drinking, diet, physical activity, body weight and infection. The next step should focus on the development of effective behavior modification programs and their implementation and dissemination.

Lower risk of progression from prediabetes to diabetes with health checkup with lifestyle education: Japan Ningen Dock study.

BACKGROUND AND AIMS: To investigate whether the progression from prediabetes to diabetes is lower among those who undertake Ningen Dock (comprehensive health checkups with lifestyle education and doctor's consultation) than those who undertake basic mandatory occupational health checkups. METHODS AND RESULTS: Subjects aged 30-69 years with complete annual data from 2008 to 2012 for either Ningen Dock or basic health checkups were enrolled. Subjects with prediabetes (fasting plasma glucose 100-125 mg/dl or HbA1c 5.7-6.4%) at baseline were selected (14,928 in the comprehensive group and 10,433 in the basic group). The incidence of diabetes (fasting plasma glucose ≥ 126 mg/dl, HbA1c ≥ 6.5% or taking glucose-lowering drugs) and the reduction of risk factors were compared. After 4 years, 3226 cases of diabetes occurred among 25,361 subjects with prediabetes. The incidence of diabetes was lower in the comprehensive group than the basic group (2.9 vs. 3.8 cases/100 person-years, hazard ratio 0.75, 95% confidence interval 0.68-0.81 after adjustment). Moreover, more overweight subjects controlled their body mass index (16.2% vs. 13.2%) and more began a daily exercise habit (11.8% vs. 8.5%) in the comprehensive group than in the basic group. The incidence of diabetes was lower in subjects who could control their weight or start daily exercise at year 1 in the comprehensive group. CONCLUSION: Progression from prediabetes to diabetes was significantly lower in subjects undertaking a comprehensive health checkup with lifestyle education. Lifestyle education at health checkup for people with prediabetes might prevent progression to diabetes by reducing modifiable risk factors.

Upper-normal waist circumference is a risk marker for metabolic syndrome in normal-weight subjects.

BACKGROUND AND AIMS: To elucidate implication of upper-normal waist circumference (WC), we examined whether the normal range of WC still represents a risk of metabolic syndrome (MetS) or non-adipose MetS components among normal-weight subjects. METHODS AND RESULTS: A total of 173,510 persons (100,386 men and 73,124 women) with normal WC (<90/80 cm in men/women) and body mass index (BMI) of 18.5-24.9 were included. Subjects were categorized as having low, moderate, and upper-normal WC for those with WC < 80, 80-84, and 85-89 cm in men and <70, 70-74, and 75-79 cm in women, respectively. The prevalence of all the non-adipose MetS components (e.g. prediabetes and borderline dyslipidemia) was significantly higher in subjects with upper-normal WC on comparison with those with low WC. Overall, the prevalence of MetS (having three or more of four non-adipose MetS components) gradually increased with increasing WC (12%, 21%, and 27% in men and 11%, 14%, and 19% in women for low, moderate, and upper-normal WC, respectively). Moreover, the risk of having a greater number of MetS components increased in subjects with upper-normal WC compared with those with low WC (odds ratios for the number of one, two, three, and four MetS components: 1.29, 1.81, 2.53, and 2.47 in men and 1.16, 1.55, 1.49, and 2.20 in women, respectively). CONCLUSION: Upper-normal WC represents a risk for acquiring a greater number of MetS components and the early stage of MetS components (prediabetes and borderline dyslipidemia), after adjusting for BMI, in a large general population with normal WC and BMI.

Effects of IL6 C-634G polymorphism on tooth loss and their interaction with smoking habits.

OBJECTIVE: To examine the association between an IL6 (Interleukin-6) polymorphism (C-634G or rs1800796) and tooth loss, and an interaction between the polymorphism and smoking habits for the loss. MATERIAL AND METHODS: Our subjects were 4917 check-up examinees ages 35-69. They reported tooth loss and lifestyle in a questionnaire. We regressed the number of teeth on the IL6 genotype, gender, age, smoking, drinking, diabetes, hypertension, physical activity, energy intake, education, and brushing. We further estimated multivariate-adjusted odds ratios (ORs) for having <20 teeth. RESULTS: Participants with a GG genotype tended to have less teeth than those with CC; ß = -0.798 (95% confidence interval [CI] = -1.501--0.096). Subjects with a GG genotype were more likely to have <20 teeth than those with CC; OR was 1.56 (95% CI = 1.08-2.25). Association between current smoking and tooth loss was stronger among those with GG than among those with CC. In a multiple regression analysis, a significant interaction was found between GG genotype and current smoking in the prediction of tooth loss (P = 0.018). CONCLUSION: The IL6 C-634G polymorphism was significantly associated with tooth loss. Our results suggest greater effects of smoking on tooth loss in GG genotype individuals.

Association of vegetable and fruit intake with gastric cancer risk among Japanese: a pooled analysis of four cohort studies.

BACKGROUND: Prospective evidence is inconsistent regarding the association between vegetable/fruit intake and the risk of gastric cancer. METHODS: In an analysis of original data from four population-based prospective cohort studies encompassing 191 232 participants, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of gastric cancer incidence according to vegetable and fruit intake and conducted a meta-analysis of HRs derived from each study. RESULTS: During 2 094 428 person-years of follow-up, 2995 gastric cancer cases were identified. After adjustment for potential confounders, we found a marginally significant decrease in gastric cancer risk in relation to total vegetable intake but not total fruit intake: the multivariate-adjusted HR (95% CI; P for trend) for the highest versus the lowest quintile of total vegetable intake was 0.89 (0.77-1.03; P for trend = 0.13) among men and 0.83 (0.67-1.03; P for trend = 0.40) among women. For distal gastric cancer, the multivariate HR for the highest quintile of total vegetable intake was 0.78 (0.63-0.97; P for trend = 0.02) among men. CONCLUSIONS: This pooled analysis of data from large prospective studies in Japan suggests that vegetable intake reduces gastric cancer risk, especially the risk of distal gastric cancer among men.

Body mass index and breast cancer risk in Japan: a pooled analysis of eight population-based cohort studies.

BACKGROUND: A positive association between body mass index (BMI) and breast cancer risk among postmenopausal women has been reported, and a weak inverse association has been suggested among premenopausal women from studies in the Western population. The effects of BMI on breast cancer have remained unclear among the Asian population, especially in premenopausal women. METHODS: We assessed the associations between BMI and breast cancer incidence by a pooled analysis from eight representative large-scale cohort studies in Japan. Cancer incidence was mainly confirmed through regional population-based cancer registries and/or through active patient notification from major local hospitals. Breast cancer was defined as code C50 according to ICD10. Pooled estimates of the hazard ratios (HRs) and 95% confidence interval (CIs) for breast cancer were calculated using random-effects models. RESULTS: Analytic subjects were 183 940 women, 1783 of whom had breast cancer during 2 194 211 person-years of follow-up. A positive association between BMI and the risk of postmenopausal breast cancer was observed (trend P<0.001). The HRs for premenopausal breast cancer were 1.05 (95% CI 0.56-1.99), 1.07 (95% CI 0.76-1.52), 0.91 (95% CI 0.64-1.30), 1.15 (95% CI 0.76-1.73), 1.45 (95% CI 0.71-2.94), and 2.25 (95% CI 1.10-4.60), respectively, in BMIs of <19, 19 to <21, 21 to <23, 25 to <27, 27 to <30, and ≥30 kg/m2. These results were not substantially altered after excluding the patients who were diagnosed with breast cancer in the first 2 years of follow-up. CONCLUSIONS: The increased risk of postmenopausal breast cancer among women with higher BMIs was confirmed in Japanese. A borderline-significant positive association between BMI and premenopausal breast cancer was observed, suggesting that body mass in Asian women might have opposite effects on breast cancer compared with Western women.

The number of metabolic syndrome components is a good risk indicator for both early- and late-stage kidney damage.

BACKGROUND AND AIMS: Renal hyperfiltration (early-stage kidney damage) and hypofiltration (late-stage kidney damage) are common in populations at high risk of chronic kidney disease. This study investigated the associations of renal hyperfiltration and hypofiltration with the number of metabolic syndrome (MetS) components. METHODS AND RESULTS: The study subjects included 205,382 people aged 40-74 years who underwent Specific Health Checkups in Aichi Prefecture, Japan. The prevalence of renal hyperfiltration [estimated glomerular filtration rate (eGFR) above the age-/sex-specific 95th percentile] and hypofiltration (eGFR below the 5th percentile) was compared according to the number of MetS components. We found that the prevalence of both hyperfiltration and hypofiltration increased with increasing number of MetS components (odds ratios for hyperfiltration: 1.20, 1.40, 1.42, 1.41, and 1.77; odds ratios for hypofiltration: 1.07, 1.25, 1.57, 1.89, and 2.21 for one, two, three, four, and five components, respectively, compared with no MetS components). These associations were observed in both normal weight [body mass index (BMI) < 25 kg/m(2)] and overweight (BMI ≥ 25 kg/m(2)) subjects. Renal hyperfiltration was associated with prehypertension and prediabetes, while hypofiltration was associated with dyslipidemia, abdominal obesity, overt hypertension, and overt diabetes. CONCLUSION: The number of MetS components is a good risk indicator of early- and late-stage kidney damage. Therefore, kidney function should be monitored in subjects with MetS components. MetS components should be treated as early as possible to prevent the development of kidney damage and cardiovascular diseases in people with hyperfiltration, regardless of their body weight.

Interaction between Habitual Green Tea and Coffee Consumption and ACTN3 Genotype in Association with Skeletal Muscle Mass and Strength in Middle-Aged and Older Adults.

BACKGROUND: Recent studies have suggested the potential benefits of habitual coffee and green tea consumption on skeletal muscle health. However, it remains unclear whether these benefits are modified by genetic factors, particularly the alpha-actinin-3 (ACTN3) genotype, which is associated with the skeletal muscle phenotype. This study aimed to investigate the interaction between habitual coffee or green tea consumption and the ACTN3 genotype in association with skeletal muscle mass (SMM) and strength. METHODS: This cross-sectional study was conducted on 1,023 Japanese middle-aged and older adults (619 females, aged 45-74 years) living in the community. SMM was gauged using a bioelectrical impedance spectroscopy device, and handgrip strength (HGS) was used to measure muscle strength. The ACTN3 genotype (RR, RX, and XX) was determined from blood samples. Sex-specific linear regression models were used to analyze the interactions between coffee or green tea consumption and the ACTN3 genotype in association with SMM and HGS. RESULTS: In females, a significant interaction was observed between green tea consumption and the ACTN3 genotype in association with HGS (P interaction < 0.05). Furthermore, stratified analysis revealed a positive association between green tea consumption and HGS, specifically in females with the ACTN3 XX genotype (P trend < 0.05). In males, no significant interactions were observed between coffee or green tea consumption and the ACTN3 genotype in association with SMM or HGS (P interaction > 0.05). CONCLUSION: Our findings suggest that the skeletal muscle strength benefits associated with habitual green tea consumption may be contingent upon sex and the ACTN3 genotype.

Association between body mass index and the colorectal cancer risk in Japan: pooled analysis of population-based cohort studies in Japan.

BACKGROUND: Obesity has been recognized as important risk factors for colorectal cancer. However, limited evidence is available on colorectal cancer and body mass index (BMI) in Asian population. METHODS: We conducted a pooled analysis of eight population-based prospective cohorts studies in Japan with more than 300,000 subjects to evaluate an impact of obesity in terms of BMI on colorectal cancer risk with unified categories. We estimated summary hazard ratio (HR) by pooling of study-specific HR for BMI categories with random effect model. RESULTS: We found a significant positive association between BMI and colorectal cancer risk in male and female. Adjusted HRs for 1 kg/m(2) increase were 1.03 [95% confidence interval (CI) 1.02-1.04] for males and 1.02 (95% CI 1.00-1.03) for females. The association was stronger in colon, especially in proximal colon, relative to rectum. Males showed a stronger association than females. Population attributable fraction for colorectal cancer by BMI ≥ 25 kg/m(2) was 3.62% (95% CI 1.91-5.30) for males and 2.62% (95% CI 0.74-4.47) for females. CONCLUSIONS: We found significant association between BMI and colorectal cancer risk by pooling of data from cohort studies with considerable number of subjects among Japanese population. This information is important in cancer control planning, especially in Asian population.

Associations of plasma IL-8 levels with Helicobacter pylori seropositivity, gastric atrophy, and IL-8 T-251A genotypes.

There are few data on circulatory pro-inflammatory cytokine levels and cytokine gene polymorphisms in H. pylori-positive patients. A cross-sectional study was conducted to examine the effects of H. pylori infection, gastric atrophy, and the IL-8 T-251A polymorphism on plasma IL-8 levels in 98 Japanese adults. Seventy-one subjects were positive for H. pylori infection. The geometric mean of plasma IL-8 concentration was significantly higher in subjects with H. pylori infection than in those without (P=0.001). The development of atrophy was negatively associated with IL-8 levels in the H. pylori-positive subjects, although not significantly. Plasma IL-8 levels in the T/T genotype were associated with H. pylori infection and atrophy status (P=0.016). Our findings suggested that circulating IL-8 levels were associated with H. pylori infection. The effect of H. pylori infection on plasma IL-8 levels was not clearly modified by the IL-8 T-251A polymorphism.

Green tea consumption and gastric cancer in Japanese: a pooled analysis of six cohort studies.

BACKGROUND: Previous experimental studies have suggested many possible anti-cancer mechanisms for green tea, but epidemiological evidence for the effect of green tea consumption on gastric cancer risk is conflicting. OBJECTIVE: To examine the association between green tea consumption and gastric cancer. METHODS: We analysed original data from six cohort studies that measured green tea consumption using validated questionnaires at baseline. Hazard ratios (HRs) in the individual studies were calculated, with adjustment for a common set of variables, and combined using a random-effects model. RESULTS: During 2 285 968 person-years of follow-up for a total of 219 080 subjects, 3577 cases of gastric cancer were identified. Compared with those drinking <1 cup/day, no significant risk reduction for gastric cancer was observed with increased green tea consumption in men, even in stratified analyses by smoking status and subsite. In women, however, a significantly decreased risk was observed for those with consumption of > or =5 cups/day (multivariate-adjusted pooled HR = 0.79, 95% confidence interval (CI) = 0.65 to 0.96). This decrease was also significant for the distal subsite (HR = 0.70, 95% CI = 0.50 to 0.96). In contrast, a lack of association for proximal gastric cancer was consistently seen in both men and women. CONCLUSIONS: Green tea may decrease the risk of distal gastric cancer in women.

A genome-wide association study of coping behaviors suggests FBXO45 is associated with emotional expression.

Individuals use coping behaviors to deal with unpleasant daily events. Such behaviors can moderate or mediate the pathway between psychosocial stress and health-related outcomes. However, few studies have examined the associations between coping behaviors and genetic variants. We conducted a genome-wide association study (GWAS) on coping behaviors in 14088 participants aged 35 to 69 years as part of the Japan Multi-Institutional Collaborative Cohort Study. Five coping behaviors (emotional expression, emotional support seeking, positive reappraisal, problem solving and disengagement) were measured and analyzed. A GWAS analysis was performed using a mixed linear model adjusted for study area, age and sex. Variants with suggestive significance in the discovery phase (N = 6403) were further examined in the replication phase (N = 7685). We then combined variant-level association evidence into gene-level evidence using a gene-based analysis. The results showed a significant genetic contribution to emotional expression and disengagement, with an estimation that the 19.5% and 6.6% variance in the liability-scale was explained by common variants. In the discovery phase, 12 variants met suggestive significance (P < 1 × 10-6 ) for association with the coping behaviors and perceived stress. However, none of these associations were confirmed in the replication stage. In gene-based analysis, FBXO45, a gene with regulatory roles in synapse maturation, was significantly associated with emotional expression after multiple corrections (P < 3.1 × 10-6 ). In conclusion, our results showed the existence of up to 20% genetic contribution to coping behaviors. Moreover, our gene-based analysis using GWAS data suggests that genetic variations in FBXO45 are associated with emotional expression.

Systematic review and meta-analysis: importance of CagA status for successful eradication of Helicobacter pylori infection.

BACKGROUND: Some, but not all studies have provided evidence that the CagA status of Helicobacter pylori strains is a predictive factor for the outcome of eradication therapy. AIM: To clarify the association between CagA status and eradication outcome. METHODS: We included studies reporting the numbers of successful and failed cases in H. pylori-eradication therapy according to the CagA status. Fourteen studies (1529 patients) were included of 325 articles identified in the search. The pooled risk ratio for H. pylori-eradication failure in CagA-negative relative to CagA-positive strains and the pooled risk difference in eradication success between the two groups were used as summary statistics. Meta-regression was used for examining the source of heterogeneity. RESULTS: The summary risk ratio for eradication failure in CagA-negative relative to CagA-positive was 2.0 (95% CI: 1.6-2.4, P < 0.001), corresponding with the summary risk difference for eradication success between the groups of 11% (95% CI: 3-19%, P = 0.011). Meta-regression analysis demonstrated that usage of polymerase chain reaction examination for CagA status and a high proportion of non-ulcer dyspepsia patients were factors for heterogeneity among studies. CONCLUSIONS: Our meta-analysis confirmed the importance of the presence of CagA as a predictor for successful eradication of H. pylori.

Prognostic factors and a scoring system for patients with skeletal metastasis.

Between 1992 and 1999, we treated 350 patients with skeletal metastases. A multivariable analysis of the patients was conducted using the Cox proportional hazards model. We identified five significant prognostic factors for survival, namely, the site of the primary lesion, the performance status (Eastern Cooperative Oncology Group status 3 or 4), the presence of visceral or cerebral metastases, any previous chemotherapy, and multiple skeletal metastases. The score for each significant factor was derived from the corresponding estimated regression coefficients (natural logarithm of the hazard ratio). The prognostic score was calculated by adding all the scores for individual factors. The rate of survival was 31% at six months and 11% at one year for the patients with a prognostic score of 6 or more. By contrast, patients with a prognostic score of 2 or less had a rate of survival of 98% at six months and 89% at one year. This scoring system can be used to determine the optimal treatment for patients with pathological fractures or epidural compression.

Modulating effect of glutathione disulfide on thyroxine-5'-deiodination by rat hepatocytes in primary culture: effect of glucose.

To investigate whether an increase in the intracellular glutathione disulfide (GSSG) concentration actually regulates T4-5'-deiodination in intact cells, rat hepatocytes in primary culture were exposed to glutathione-oxidizing agents (diamide and tertiary butylhydroperoxide) or vinblastine, and their effects on 5'-deiodination of T4 were studied. Deiodinating activity was determined from the 125I- fraction released from [3',5'-125I]T4 added to the serum-free culture medium. Total glutathione (T-GSH) and GSSG levels were determined enzymatically. Diamide (1 mM) and tertiary butylhydroperoxide (0.5 mM) increased the GSSG fraction to approximately 40% of the T-GSH at 5 min, followed by a rapid decrease in GSSG. Glucose deprivation of the medium caused a greater GSSG level at 5 min, followed by a delayed normalization of the increased GSSG level. T4-5'-deiodinating activity was minimally decreased in hepatocytes exposed to 1 mM diamide in the presence of glucose in the medium, but was significantly inhibited in the absence of glucose. Vinblastine, in contrast, gradually and steadily increased the GSSG fraction, and by 3 h, GSSG exceeded 20% of T-GSH (at 10(-4) M vinblastine). This was accompanied by a significant inhibition of 5'-deiodinating activity. When the enzyme activity was inhibited, the T-GSH level was decreased to 40-80% of the control level, which per se cannot account for the decreased T4-5'-deiodinating activity, as reported previously. These data suggest that the increased GSSG level, but not the T-GSH concentration, modulates T4-5'-deiodination in intact cells, and that glucose stimulates the enzyme activity by maintaining glutathione in the reduced form, probably through supplying NADPH, a cofactor for GSSG reductase.

Processing of human growth hormone by rat hepatocytes in monolayer culture.

The fate of cell-bound [125I]iodo-human GH ([125I]iodo-hGH) was studied in monolayer cultures of hepatocytes from pregnant and nonpregnant rats. Both the binding of [125I]iodo-hGH and its degradation were significantly higher in cells from pregnant than from nonpregnant rats. The positive correlation between the number of binding sites for hGH and the amount of degradation of [125I]iodo-hGH suggests that degradation, at least in part, is a receptor-mediated process. Degradation as a time- and temperature-dependent process was impaired by lysosomotropic compounds such as chloroquine and NH4Cl in a dose-dependent manner. Dinitrophenol, N-ethyl-maleimide, and NaN3 were also effective in preventing degradation, suggesting that an energy-requiring process is involved in degradation of [125I]iodo-hGH. Cell-bound [125I]iodo-hGH became less dissociable as a function of time of association. Degradation of [125I]iodo-hGH accelerated the dissociation of cell-bound radioactivity. Gel-filtration experiments revealed that [125I]iodo-hGH is degraded to smaller molecular species, but only a small portion of the degradation products exists within the cells. These observations suggest that receptor-bound [125I]iodo-hGH is degraded by an internalization process; lysosomal enzymes are probably responsible for the degradation of [125I]iodo-hGH, and the degraded products are rapidly released into the extracellular space.

Thyroid volume and serum thyroglobulin levels in patients with acromegaly: correlation with plasma insulin-like growth factor I levels.

The pathogenesis of the goiter that is frequently found in patients with acromegaly is not known. Using ultrasonic scanning, we measured thyroid volume in 17 euthyroid patients with acromegaly and examined the relationships among thyroid size, plasma GH and insulin-like growth factor (IGF-I) levels, and serum thyroglobulin (TG) levels. The mean estimated thyroid volume in these 17 patients was 32.8 +/- 15.5 (+/- SD) mL, significantly larger than that in normal subjects (15.4 +/- 3.1 mL), and 64.7% of the patients had multinodular goiter, as identified by ultrasonography. Thyroid volume was positively correlated with plasma GH and IGF-I levels and heel-pad thickness, but not with the serum TSH level. In 7 patients, thyroid volume decreased in association with a decline in plasma GH and IGF-I levels after surgical treatment. The serum TG level was elevated in 7 of the 15 patients in whom it was measured, and the mean value was 51.7 +/- 62.7 (+/- SD) micrograms/L (normal, 12.6 +/- 6.4 micrograms/L). We found no correlations among the serum TG and TSH levels, plasma GH and IGF-I concentrations, and/or thyroid volume. However, serum TG decreased after surgical treatment, just as did plasma IGF-I. These observations together with the results of recent in vitro studies by others suggest that IGF-I is one of the factors involved in goiter formation, but the elevated serum TG levels in acromegaly are controlled not only by IGF-I but also by other factors.

Association of Ile462Val (Exon 7) polymorphism of cytochrome P450 IA1 with lung cancer in the Asian population: further evidence from a case-control study in Okinawa.

Okinawa, a group of islands that lie between the East China Sea and the Pacific Ocean, 2000 km south of the Japanese main islands, has a different profile of diseases, ethnicities, and cultures than does the rest of Japan. We examined an Ile462Val polymorphism (CYP1A1*2 allele) of cytochrome P450 IA1 in a hospital-based case-control study of lung cancer patients (247 cases and 185 controls) in Okinawa to ascertain the association of this variant with lung cancer. In addition, the distribution of this genotype was studied in populations from different areas of Japan, including Tokyo (n = 69) and Iwate (northern part of Japan; n = 81), as well as in a Chinese group from the Jiangsu province (n = 39) and in an Australian Caucasian group (n = 146). Genotype frequency in controls was not significantly different from area to area in Japan. In Okinawa, however, the genotype encoding Val/Val was associated with a significantly higher risk of lung cancer (odds ratio = 3.32, P = 0.013), especially of squamous cell carcinoma and small cell carcinoma (odds ratio = 4.85 and 9.35, respectively). The Val-encoding allele was less frequent in the Chinese population and was rare in Australian Caucasians. Thus, this study gives support to the value of the cytochrome P450 IA1 Ile462Val polymorphism as a practical high-risk marker of lung cancer in populations, especially those in southeast Asia, in which this variant is more common.

hOGG1 Ser326Cys polymorphism and lung cancer susceptibility.

The human homologue of the yeast OGG1 gene, hOGG1, has been cloned, and its genetic structure has been determined. Several polymorphisms in the hOGG1 gene were detected in the Japanese populations, and among them, the Ser-Cys polymorphism at codon 326 has been shown to have a functional difference in complementation of mutant Escherichia coli that is defective in the repair of 8-hydroxyguanine. Activity in the repair of 8-hydroxyguanine is greater in hOGG1-Ser326 protein than in hOGG1(326) protein. Because many environmental carcinogens produce 8-hydroxyguanine residue and mismatching to this modified base potentially causes oncogenic mutations, the capacity to repair these lesions can be involved in cancer susceptibility in human beings. We, therefore, examined allele distributions of the Ser326Cys polymorphism in a case-control study of male lung cancer in Okinawa. The analyses based on 241 cases and 197 hospital controls disclosed the following findings. (a) Those with the Cys/Cys genotype were at an increased risk of squamous cell carcinoma and nonadenocarcinoma compared to those with the Ser/Cys and those with the Ser/Ser genotypes combined. The odds ratios adjusted for age and smoking history were 3.01 (95% confidence interval, 1.33-6.83) and 2.18 (95% confidence interval, 1.05-4.54), respectively. (b) The odds ratios for other histological subtypes of lung cancer or those in total were not significant. Those for Cys/Cys or Ser/Cys genotype against Ser/Ser did not reach statistical significance in any cell type. (c) The distributions of this polymorphism varied for different populations (Chinese, Japanese, Micronesians, Melanesians, Hungarians, and Australian Caucasians), with much less prevalence of Cys allele in the latter three populations. Although our sample size was limited, these results indicate that the Ser326Cys variant may be related to squamous cell lung cancer susceptibility. The Cys/Cys genotype appears to be more susceptible to squamous cell carcinoma, although the risk is less than that previously reported to be associated with the CYP1A1 gene. Further studies are needed to assess the importance of the interpopulation variation to cancer susceptibility.