Genetic polymorphisms of 17 ß-hydroxysteroid dehydrogenase 3 and the risk of hypospadias.

INTRODUCTION: Hypospadias is a common congenital anomaly caused by incomplete fusion of urethral folds. Development of the urethra and external genital system in the male fetus is an androgen-dependent process. In this regard, enzymes 17 ß-hydroxysteroid dehydrogenase type 3 (17 ß HSD3, encoded by HSD17B3) and steroid 5 α-reductase type 2 (encoded by SRD5A2) play crucial roles. AIM: To investigate the possible associations between common polymorphisms in HSD17B3 as well as well-known V89L polymorphism in SRD5A2 and risk of hypospadias. METHODS: A case-control study was performed between 1999 and 2005. There were 89 Japanese boys with hypospadias and 291 newborn controls. We genotyped HSD17B3-1999T>C, +10A>G, +20A>G, +139G>A (V31I), +913G>A (G289S), and SRD5A2+336G>C (V89L) polymorphisms by allelic discrimination assay. We measured mRNA expression of the wildtype G289 allele and the mutant S289 allele of the HSD17B3 gene in the transfected human fetal kidney HEK293 cells. MAIN OUTCOME MEASURES: Assessment of hypospadias including its severity and HSD17B3 and SRD5A2 genes using DNA blood samples: allele and genotype distribution of single nucleotide polymorphisms in these two genes in cases and controls. RESULTS: In our study, the risk of hypospadias was significantly higher in subjects carrying homozygous HSD17B3+913A (289S) alleles (odds ratio [OR]: 3.06; 95% confidence interval [CI]: 1.38-6.76). The risk of severe hypospadias was much higher in these subjects (OR: 3.93; 95% CI: 1.34-11.49). The mRNA expression levels of HSD17B3 G289 were higher than those of HSD17B3 S289 mutant (P < 0.001). In addition, the risk of severe hypospadias increased in boys carrying the SRD5A2+336C (89L) allele (OR: 3.19; 95% CI: 1.09-9.36). CONCLUSIONS: These results suggest that the HSD17B3 G289S polymorphism may be a potential risk modifier for hypospadias. Our findings provide evidence that a certain genotype related to androgen production may potentiate risk of hypospadias.

Isoflavone consumption and subsequent risk of hepatocellular carcinoma in a population-based prospective cohort of Japanese men and women.

The incidence of hepatocellular carcinoma (HCC) is much higher in men than in women. Several experiment and epidemiological studies have suggested that estrogen might play an inhibitory role in the development of HCC. Because isoflavones have a similar structure as 17beta-estradiol and appear to have an anti-estrogenic effect in women and estrogenic effect in men, we hypothesized that the effect of isoflavones on HCC differs by sex. We investigated the association between isoflavones (genistein and daidzein) and soy products and HCC in Japan in a population-based prospective study in 19,998 Japanese (7,215 men and 12,783 women) aged 40-69 years. During 11.8 years of follow-up, 101 subjects (69 men and 32 women) were newly diagnosed with HCC. Case patients were grouped according to consumption of isoflavones and soy products and stratified by hepatitis virus infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC were calculated by Cox proportional-hazards modeling. In women, genistein and daidzein were dose-dependently associated with an increased risk of HCC, with multivariable HRs for the highest versus lowest tertile of 3.19 (95%CI = 1.13-9.00, p(trend) = 0.03) and 3.90 (95% CI = 1.30-11.69, p(trend) = 0.01), respectively. No association between isoflavones and HCC was observed in men. These results persisted when analysis was restricted to subjects positive for either or both hepatitis C and B virus. In conclusion, isoflavone consumption may be associated with an increased risk of HCC in women. Women with hepatitis virus infection may be advised to abstain from isoflavone consumption. Further studies are warranted to confirm these findings.

Coffee, green tea, and caffeine consumption and subsequent risk of bladder cancer in relation to smoking status: a prospective study in Japan.

Coffee and caffeine consumption are thought to increase the risk of bladder cancer. However, few studies have stratified this risk by smoking status, which is a potential confounder. Here, we investigated the association between coffee, green tea (another major source of caffeine), and caffeine, and bladder cancer incidence in relation to smoking status. We conducted a population-based prospective study in a cohort of Japanese, comprising a total of 49 566 men and 54 874 women aged 40­69 years who reported their coffee and green tea consumption at baseline. During follow-up from 1990 through 2005, 164 men and 42 women were newly diagnosed with bladder cancer. Cigarette smoking was associated with an increased risk of bladder cancer, with a strong dose­response relationship. Coffee was positively associated with bladder cancer risk in men, without statistical significance. When stratified by smoking status, coffee and caffeine consumption were associated with an increased risk of bladder cancer in never- or former-smoking men, with hazard ratios (95% confidence interval) in the highest categories of coffee (one or more cups per day) and caffeine consumption compared with the lowest of 2.24 (95% CI = 1.21­4.16) and 2.05 (95% CI = 1.15­3.66), respectively. In conclusion, cigarette smoking was confirmed as a risk factor for bladder cancer. Coffee and caffeine may be associated with an increased bladder cancer risk in never or former smokers among Japanese men.

Visceral fat volume and the prevalence of colorectal adenoma.

Few epidemiologic investigations of visceral adiposity and colorectal neoplasms have attempted the direct quantification of visceral fat. The authors measured visceral fat volume among middle-aged and elderly Japanese men and women who underwent colonoscopy and positron emission tomography/computed tomography for cancer screening in Tokyo, Japan, between February 2004 and February 2005, and examined the association between visceral adiposity and colorectal adenoma in 1,205 eligible subjects. Odds ratios and 95% confidence intervals for colorectal adenoma were estimated by using an unconditional logistic regression model after adjustment for potential confounders. Despite its high correlation with body mass index, visceral fat volume was associated with the prevalence of colorectal adenoma independently of body mass index in both sexes. After further adjustment for body mass index, the odds ratio of colorectal adenoma for the highest compared with the lowest quartile of visceral fat volume was 1.58 (95% confidence interval: 1.11, 2.24) for men and women combined. Conversely, body mass index was unlikely to modify the association between visceral fat volume and colorectal adenoma (P(interaction) = 0.39). These findings add to accumulating evidence that visceral adiposity exerts an important influence on the pathogenesis of colorectal neoplasms. The mechanisms of this potential association between visceral adiposity and colorectal carcinogenesis warrant further investigation.

Metabolic factors and subsequent risk of hepatocellular carcinoma by hepatitis virus infection status: a large-scale population-based cohort study of Japanese men and women (JPHC Study Cohort II).

OBJECTIVE: The association between metabolic factors and hepatocellular carcinoma (HCC) has not been well clarified. We prospectively examined whether metabolic factors predicts the subsequent risk of HCC in the Japan Public Health Center-based Prospective Study Cohort II, in consideration of hepatitis virus infection status. METHODS: A total of 17,590 subjects aged 40-69 participating in a questionnaire and health checkup survey during 1993-1994 were followed for incidence of HCC through 2006. A total of 102 cases of HCC were newly documented. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for metabolic factors controlling for potential confounding factors. RESULTS: The presence of metabolic factors in the aggregate was associated with a significantly increased risk of HCC, especially with hepatitis virus infection. HCC was positively associated particularly with high glucose (HR = 1.75, CI = 1.11-2.74) and overweight (HR = 2.22, CI = 1.42-3.48). Results were similar when analyses were limited to subjects with HCV infection. CONCLUSIONS: Although metabolic factors in the aggregate may be associated with an increased risk of HCC, the main contributors to this association under HCV infection appear to be overweight and high glucose. Improvement of these factors may be a crucial target in preventing progression to HCC in those with HCV infection.

Genetic polymorphisms in estrogen metabolism and breast cancer risk in case-control studies in Japanese, Japanese Brazilians and non-Japanese Brazilians.

Although many studies have examined associations between single nucleotide polymorphisms (SNPs) in the CYP1A1, CYP1A2 and CYP1B1 genes and breast cancer risk, no study has examined functional SNPs in the CYP3A5 gene and only a small number of studies have been investigated in Japanese populations. To examine the association between six SNPs, CYP1A1(*)2A, CYP1A1(*)2C, CYP1A2(*)1F, CYP1B1 Arg(48)Gly, CYP1B1 Leu(432)Val and CYP3A5*3 and breast cancer risk, therefore, we conducted hospital-based case-control studies in Nagano, Japan and São Paulo, Brazil including 873 pairs (403 Japanese (JJ), 81 Japanese Brazilians (JB) and 389 non-Japanese Brazilians (NJB)). Although we found no significant association in the three populations combined, subgroup analyses revealed statistically significant associations of CYP1A2*1F in NJB, and CYP1B1 Leu(432)Val and CYP3A5*3 in JJ with breast cancer risk. Compared to women with the AA genotype in CYP1A2*1F, the odds ratio (OR) (95% confidence interval (CI)) for NJB with the CC genotype was 0.54 (0.32-0.90); that for JJ with Leu/Val+Val/Val versus Leu/Leu genotype in CYP1B1 Leu(432)Val was 0.68 (0.48-0.97); and that for JJ with (*)3/(*)1+(*)1/(*)1 versus (*)3/(*)3 genotype in CYP3A5*3 was 1.49 (1.10-2.04). Our findings provide further evidence that genetic polymorphisms related to estrogen metabolism may play a role in the development of breast cancer.

Calcium intake and the 10-year incidence of self-reported vertebral fractures in women and men: the Japan Public Health Centre-based Prospective Study.

The purpose of this study was to evaluate the effect of low Ca intake on the 10-year incidence of vertebral fractures in cohorts I and II of the Japan Public Health Centre-based Prospective Study. The baseline studies were conducted in 1990-1994, with the follow-up studies conducted after 10 years. We analysed 33,970 subjects aged 40-59 years in cohort I and 41,664 subjects aged 40-69 years in cohort II. At baseline, the intake of Ca was assessed as a predictor, using validated FFQ. A meta-analysis was performed to estimate a summary relative risk (RR) for the two cohort studies. The 10-year cumulative incidences of self-reported vertebral fractures were 0.38% for cohort I and 0.56% for cohort II. In women, lower Ca intake was associated with a higher incidence of vertebral fractures (P for trend=0.001), with the lowest quartile of Ca intake having a significantly higher incidence (0.89/1000 persons per year or RR 2.10 (95% CI 1.25, 3.55)) than that (0.42/1000 persons per year) of the highest. In addition, the RR calculated using energy-adjusted Ca intake (by the residual method) as an outcome was 1.92 (95% CI 1.28, 2.88). However, no such association was observed in men. An increase of Ca intake should be considered as a preventive strategy for vertebral fractures in peri- and post-menopausal women with a low Ca intake.

Plasma levels of carotenoids, retinol and tocopherol and the risk of gastric cancer in Japan: a nested case-control study.

Fruits and vegetables have been suggested to confer protection against diseases such as cancer through the effects of antioxidants, often represented by carotenoids. We investigated the impact of carotenoids, retinol and tocopherol on gastric cancer development in a large nested case-control study among Japanese with known Helicobacter pylori infection status. A total of 36 745 subjects aged 40-69 in the Japan Public Health Center-based Prospective Study who responded to the baseline questionnaire and provided blood samples in 1990-1995 were followed until 2004. Plasma levels of carotenoids in 511 gastric cancer cases and 511 matched controls were measured by high-performance liquid chromatography. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression models. Plasma level of beta-carotene was inversely associated with the risk of gastric cancer (compared with the lowest quartile: OR = 0.63, 95% CI = 0.31-0.75; OR = 0.48, 95% CI = 0.31-0.75 and OR = 0.46, 95% CI = 0.28-0.75, for quartile 2, 3 and 4, respectively, P(trend) < 0.01). Inverse associations were evident in men for alpha-carotene (P(trend) = 0.04) and beta-carotene (P(trend) < 0.01), but not in women, who had relatively higher plasma levels compared with men. We found no statistically significant association between plasma levels of lutein/zeaxanthin, lycopene, retinol, alpha- or gamma-tocopherol and gastric cancer risk. Our findings suggest that those who have very low plasma levels of alpha-carotene and beta-carotene are at a higher risk of gastric cancer.

Fruit and vegetable consumption and squamous cell carcinoma of the esophagus in Japan: the JPHC study.

Epidemiological studies have consistently demonstrated a decrease in the risk of esophageal squamous cell carcinoma (SCC) associated with higher fruit and vegetable intake, although the association has been examined predominantly in case-control studies. Here, we conducted a population-based prospective cohort study among middle-aged Japanese men. Lifestyle characteristics were investigated using a self-administered questionnaire, which included a validated food frequency questionnaire with 138 food and beverage items. We followed a total of 38,790 men aged 45-74 years. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for esophageal SCC, with adjustment for potential confounders. During 297,651 person-years of follow-up, a total of 116 men were newly diagnosed with esophageal SCC. An increase in consumption of total fruit and vegetables by 100 grams per day (g/day) was associated with an 11% decrease in the incidence of esophageal SCC (95% CI: 1-21%). In particular, a higher intake of cruciferous vegetables was associated with a significant decrease in risk (HR per 100 g/day: 0.44; 95% CI: 0.23-0.82). Stratified analyses revealed that the beneficial effect of fruits and vegetables was not able to completely offset the harmful effect of tobacco and alcohol. Our findings provide further evidence for the protective role of fruits and vegetables in the development of esophageal SCC. To effectively reduce the burden of this disease, however, priority should be placed on smoking and drinking cessation. Finally, cruciferous vegetables deserve further investigation as foods possibly effective in the prevention of esophageal SCC.

Coffee consumption and risk of endometrial cancer: a prospective study in Japan.

Coffee has been proposed to decrease the circulating insulin and estrogen levels, which are related to the development of endometrial cancer. However, few studies have prospectively assessed the association between coffee consumption and endometrial cancer. We conducted a population-based prospective cohort study in 53,724 Japanese women aged 40-69 years with no history of cancer at baseline in 1990-1994. We used Cox proportional hazards regression analysis to estimate the hazard ratio (HR) and 95% confidence interval (CI) of endometrial cancer incidence in relation to coffee consumption. All reported p values are 2-tailed. During the 15-year follow-up period, we documented 117 cases of endometrial cancer. Coffee consumption was significantly associated with a decreased risk of endometrial cancer. After adjustment for age, study area, body mass index, menopausal status, age at menopause for postmenopausal women, parity, use of exogenous female hormones, smoking status and by consumption of green vegetables, beef, pork and green tea, the multivariate HRs (95% CI) of endometrial cancer in women who drank coffee /=3 cups/day were 1.00, 0.97 (0.56-1.68), 0.61 (0.39-0.97) and 0.38 (0.16-0.91), respectively (p for trend = 0.007). In contrast, green tea consumption was not significantly associated with a reduced risk of endometrial cancer (p for trend = 0.22). The inverse association between coffee consumption and risk of endometrial cancer was consistently observed in subgroup analyses stratified by potential confounders. Coffee consumption may be associated with a decreased risk of endometrial cancer.

Passive smoking and lung cancer in Japanese non-smoking women: a prospective study.

Although smoking is a major cause of lung cancer, the proportion of lung cancer cases among Japanese women who never smoked is high. As the prevalence of smoking in Japan is relatively high in men but low in women, the development of lung cancer in non-smoking Japanese women may be significantly impacted by passive smoking. We conducted a population-based prospective study established in 1990 for Cohort I and in 1993 for Cohort II. The study population was defined as all residents aged 40-69 years at the baseline survey. 28,414 lifelong non-smoking women provided baseline information on exposure to tobacco smoke from their husband, at the workplace and during childhood. Over 13 years of follow-up, 109 women were newly diagnosed with lung cancer, of whom 82 developed adenocarcinoma. Compared with women married to never smokers, hazard ratio (HR) [95% confidence interval (CI)] for all lung cancer incidence in women who lived with a smoking husband was 1.34 (95% CI 0.81-2.21). An association was clearly identified for adenocarcinoma (HR 2.03, 95% CI 1.07-3.86), for which dose-response relationships were seen for both the intensity (p for trend = 0.02) and amount (p for trend = 0.03) of the husband's smoking. Passive smoking at the workplace also increased the risk of lung cancer (HR 1.32, 95% CI 0.85-2.04). Moreover, a higher risk of adenocarcinoma was seen for combined husband and workplace exposure (HR 1.93, 95% CI 0.88-4.23). These findings confirm that passive smoking is a risk factor for lung cancer, especially for adenocarcinoma among Japanese women.

Green tea consumption and prostate cancer risk in Japanese men: a prospective study.

The incidence of prostate cancer is much lower in Asian than Western populations. Given that environmental factors such as dietary habits may play a major role in the causation of prostate cancer and the high consumption of green tea in Asian populations, this low incidence may be partly due to the effects of green tea. The JPHC Study (Japan Public Health Center-based Prospective Study) was established in 1990 for cohort I and in 1993 for cohort II. The subjects were 49,920 men aged 40-69 years who completed a questionnaire that included their green tea consumption habit at baseline and were followed until the end of 2004. During this time, 404 men were newly diagnosed with prostate cancer, of whom 114 had advanced cases, 271 were localized, and 19 were of an undetermined stage. Green tea was not associated with localized prostate cancer. However, consumption was associated with a dose-dependent decrease in the risk of advanced prostate cancer. The multivariate relative risk was 0.52 (95% confidence interval: 0.28, 0.96) for men drinking 5 or more cups/day compared with less than 1 cup/day (p(trend) = 0.01). Green tea may be associated with a decreased risk of advanced prostate cancer.

Daily total physical activity level and total cancer risk in men and women: results from a large-scale population-based cohort study in Japan.

The impact of total physical activity level on cancer risk has not been fully clarified, particularly in non-Western, relatively lean populations. The authors prospectively examined the association between daily total physical activity (using a metabolic equivalents/day score) and subsequent cancer risk in the Japan Public Health Center-based Prospective Study. A total of 79,771 general-population Japanese men and women aged 45-74 years who responded to a questionnaire in 1995-1999 were followed for total cancer incidence (4,334 cases) through 2004. Compared with subjects in the lowest quartile, increased daily physical activity was associated with a significantly decreased risk of cancer in both sexes. In men, hazard ratios for the second, third, and highest quartiles were 1.00 (95% confidence interval (CI): 0.90, 1.11), 0.96 (95% CI: 0.86, 1.07), and 0.87 (95% CI: 0.78, 0.96), respectively (p for trend = 0.005); in women, hazard ratios were 0.93 (95% CI: 0.82, 1.05), 0.84 (95% CI: 0.73, 0.96), and 0.84 (95% CI: 0.73, 0.97), respectively (p for trend = 0.007). The decreased risk was more clearly observed in women than in men, especially among the elderly and those who regularly engaged in leisure-time sports or physical exercise. By site, decreased risks were observed for cancers of the colon, liver, and pancreas in men and for cancer of the stomach in women. Increased daily physical activity may be beneficial in preventing cancer in a relatively lean population.

Fruit and vegetable intake and risk of total cancer and cardiovascular disease: Japan Public Health Center-Based Prospective Study.

Few studies have investigated the effects of fruit and vegetables on the risk of both cancer and cardiovascular disease (CVD). The authors examined associations between fruit and vegetable consumption and risk of total cancer and CVD in the same Japanese population. During 1995-1998, a validated food frequency questionnaire was administered in nine areas to 77,891 men and women aged 45-74 years. During as many as 459,320 person-years of follow-up until the end of 2002, 3,230 cancer cases and 1,386 CVD cases were identified. Higher consumption of fruit, but not vegetables, was associated with significantly lower risk of CVD: multivariate hazard ratios for the highest versus lowest quartiles of intake were 0.81 (95% confidence interval (CI): 0.67, 0.97; trend p = 0.01) for fruit and 0.97 (95% CI: 0.82, 1.15; trend p = 0.66) for vegetables. Consumption of fruit or vegetables was not associated with decreased risk of total cancer: corresponding hazard ratios were 1.02 (95% CI: 0.90, 1.14; trend p = 0.95) for fruit and 0.94 (95% CI: 0.84, 1.05; trend p = 0.16) for vegetables. This prospective cohort study demonstrated that, in the Japanese population, consumption of fruit is associated with lower risk of CVD, whereas fruit or vegetables may not be associated with lower risk of total cancer.

Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men.

Many epidemiologic studies have reported a positive association between dairy products and prostate cancer. Calcium or saturated fatty acid in dairy products has been suspected as the causative agent. To investigate the association between dairy products, calcium, and saturated fatty acid and prostate cancer in Japan, where both the intake of these items and the incidence of prostate cancer are low, we conducted a population-based prospective study in 43,435 Japanese men ages 45 to 74 years. Participants responded to a validated questionnaire that included 138 food items. During 7.5 years of follow-up, 329 men were newly diagnosed with prostate cancer. Dairy products were associated with a dose-dependent increase in the risk of prostate cancer. The relative risks (95% confidence intervals) comparing the highest with the lowest quartiles of total dairy products, milk, and yogurt were 1.63 (1.14-2.32), 1.53 (1.07-2.19), and 1.52 (1.10-2.12), respectively. A statistically significant increase in risk was observed for both calcium and saturated fatty acid, but the associations for these were attenuated after controlling for potential confounding factors. Some specific saturated fatty acids increased the risk of prostate cancer in a dose-dependent manner. Relative risks (95% confidence intervals) on comparison of the highest with the lowest quartiles of myristic acid and palmitic acid were 1.62 (1.15-2.29) and 1.53 (1.07-2.20), respectively. In conclusion, our results suggest that the intake of dairy products may be associated with an increased risk of prostate cancer.

Dietary soy and isoflavone intake and risk of colorectal cancer in the Japan public health center-based prospective study.

Several experimental studies have reported that the anticarcinogenic properties of dietary soy play an important role in preventing colorectal cancer. However, few epidemiologic studies have examined this association in general populations and their findings have been inconsistent. We investigated the association between dietary soy and isoflavone intake and incidence of colorectal cancer in a prospective cohort study of 83,063 Japanese men and women, ages 45 to 74 years. Dietary soy and isoflavone intake was measured through a validated food frequency questionnaire in 1995 and 1998. Throughout 2004, a total of 886 cases of colorectal cancer were newly identified (291 proximal colon, 286 distal colon, and 277 rectum). The hazard ratios and 95% confidence intervals (95% CIs) were estimated by fitting a Cox proportional hazards model. The intake of isoflavones, miso soup, and soy food was not associated with colorectal cancer in either men or women. By colorectal cancer subsite, the risk of proximal colon cancer in men decreased with increasing consumption of isoflavones, miso soup, and soy food. Compared with men in the lowest quartiles of isoflavones, miso soup, and soy food intake, the hazard ratios in the highest quartiles were 0.55 (95% CI, 0.33-0.92), 0.72 (95% CI, 0.43-1.21), and 0.51 (95% CI, 0.30-0.87), respectively. The results showed no association for distal colon and rectal cancer in men or for subsites of colorectal cancer in women. These findings suggest that the intake of isoflavones, miso soup, and soy food has no substantial effect on the risk of colorectal cancer in Japanese men and women.

Alcohol and risk of lung cancer among Japanese men: data from a large-scale population-based cohort study, the JPHC study.

OBJECTIVE: Although large-scale studies, including meta-analyses, on the association between alcohol consumption and lung cancer have been reported, the risk of lung cancer in extremely high consumption groups (>or=450 g ethanol/week) in both current smokers and nonsmokers remains unclear. Here, we investigated the association between alcohol consumption and lung cancer incidence. METHODS: We conducted a population-based prospective cohort study in 46,347 Japanese men aged 40-69 years with no history of cancer at baseline in 1990-1994. We used Cox proportional hazards regression analysis to estimate the hazard ratio (HR) and 95% confidence interval (CI) of lung cancer incidence according to alcohol consumption. RESULTS: During the 14-year follow-up period, we documented 651 cases of lung cancer. We found a positive association between alcohol consumption and lung cancer risk confined to current smokers. Compared with occasional drinkers, the multivariate HRs (95% CI) in the highest category (>or=450 g ethanol/week) were 1.31 (0.89-1.94) among total participants, 0.58 (0.26-1.30) (p for trend = 0.49) among nonsmokers, and 1.69 (1.05-2.72) (p for trend = 0.02) among current smokers. CONCLUSIONS: Among this population with a large variation in alcohol consumption, alcohol consumption was not an independent risk factor for lung cancer except for current smokers.

Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias.

BACKGROUND: The etiology of hypospadias is regarded as a complex disorder with both genetic and environmental contributions. Although alterations in androgen activity have been associated with hypospadias, few associations with estrogen activity have been documented. Here, we assessed genetic polymorphisms in estrogen receptor genes and their association with hypospadias. METHODS: Using a case-control study of 59 cases with hypospadias and 286 controls, we examined the association of hypospadias with the following polymorphisms: PvuII and XbaI in ESR1, and 2681-4A>G in ESR2. RESULTS: For the cases, we found a negative association with the G allele containing variants of ESR1 XbaI (OR = 0.52, P < 0.05), and a negative association with the G allele containing variants of ESR2 2681-4A>G (OR = 0.59, P < 0.05). For the cases, we also identified a negative association with the CG haplotype, and a positive association with the CA haplotype, defined by ESR1 PvuII and XbaI (P < 0.05). CONCLUSIONS: These findings suggest that the G allele containing variants of ESR1 XbaI and the G allele containing variants of ESR2 2681-4A>G may decrease the risk of hypospadias, whereas the ESR1 C-A haplotype may increase its risk.

Education in relation to incidence of and mortality from cancer and cardiovascular disease in Japan.

BACKGROUND: Although lower education has been associated with poorer health, few studies have examined whether lower education affects mortality, incidence, both or neither of cancer and cardiovascular disease. METHODS: The authors conducted a population-based prospective cohort study among 39,228 men and women who were aged 40-59 years and lived in four areas in Japan. Information on education and lifestyle variables were obtained by a self-administered questionnaire in 1990. Follow-up until the end of 2002 (for incidence) or 2003 (for mortality) ascertained 2573 and 1251 incident cases of cancer and cardiovascular disease, respectively, and 2430 deaths (1064 from cancer, 548 from cardiovascular disease and 818 from other causes). RESULTS: After adjustment for demographic and lifestyle variables, <10 years of education, as compared with >12 years of education, was associated with significantly higher mortality from all causes [hazard ratio (HR) = 1.22, 95% confidence interval (CI): 1.05-1.42] and cardiovascular disease (HR = 1.44, 95% CI: 1.01-2.06), but was not associated with higher incidence of cardiovascular disease (HR = 0.96, 95% CI: 0.78-1.18) or higher mortality or incidence of cancer. CONCLUSION: The findings suggest that lower education is associated with higher mortality from all causes and cardiovascular disease among the Japanese population that is not totally attributable to lifestyle differences or higher cardiovascular disease incidence.

Plasma organochlorine levels and subsequent risk of breast cancer among Japanese women: a nested case-control study.

To our knowledge, no prospective study has examined the association between blood levels of organochlorines and breast cancer risk in Asian countries. Here, we tested the hypothesis that higher blood levels of organochlorines are associated with an increased risk of breast cancer in Japanese women. A total of 24,226 women subjects of the Japan Public Health Center-based Prospective Study aged 40 to 69 years who responded to the baseline questionnaire and provided blood in 1990-1995 were followed to December 2002. During 10.7 years follow-up, 144 cases of breast cancer were newly diagnosed. Two matched-controls for each case were selected from the cohort. Plasma levels of p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), and beta-hexachlorocyclohexane (beta-HCH) were measured. A conditional logistic regression was used to estimate the odds ratio (OR) of breast cancer according to cholesterol-adjusted organochlorine levels based on 139 matched pairs. We found no statistically significant positive association between plasma organochlorine level and breast cancer risk. Adjusted ORs for p,p'-DDT, HCB, and beta-HCH were less than 1. For p,p'-DDE, adjusted OR for the highest versus lowest quartile was 1.48 (95% confidence interval 0.70-3.13; p for trend=0.25). A stratified analysis by menopausal status showed positive associations for p,p'-DDT and p,p'-DDE in premenopausal but not postmenopausal women, although without statistical significance. Our data do not support the hypothesis that plasma levels of p,p'-DDT, p,p'-DDE, HCB, and beta-HCH are associated with an overall increased risk of breast cancer among Japanese women.