Norie Sawada

The JPHC Study: Design and Some Findings on the Typical Japanese Diet

The Japan Public Health Center-based prospective Study conducted a baseline survey for 140 000 registered residents aged 40-69 years within 11 public health center areas nationwide in 1990-94. Five- and 10-year follow-up surveys were conducted to update information on lifestyle habits and health conditions. In total, 130 000 participants responded to at least one of the three questionnaire surveys, and 78 000 to all three. In addition, 60 000 participants provided blood samples on at least one of the two sampling times, and 23 000 on both. The subjects have been followed for vital status and the occurrence of cancer and other diseases. As of December 2011, 24 000 deaths have been documented, as well as 17 000 cases of cancer, 6000 cases of stroke and 1100 cases of myocardial infarction. We have tested the association between potential causal factors and the incidence of or mortality from cancer and other diseases, and published >250 papers to date. Typical dietary habits in Japan are high consumption of soy/isoflavones, fish/n-3 fatty acids, salt/salted foods and green tea, and low consumption of red meat and saturated fat. This paper briefly summarizes the observed associations of these foods/nutrients with cancer, cardiovascular diseases and diabetes. The Japan Public Health Center-based prospective Study is scheduled to conduct active follow-up for a total of 30 years, and we plan to publish additional evidence on the potential causes of a shorter life and major disease occurrence.

Consumption of n-3 Fatty Acids and Fish Reduces Risk of Hepatocellular Carcinoma

BACKGROUND & AIMS Fish is a rich source of n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). Although consumption of fish and n-3 PUFA has been reported to protect against the development of some types of cancer, little is known about its association with hepatocellular carcinoma (HCC). METHODS We investigated the association between fish and n-3 PUFA consumption and HCC incidence (n = 398) in a population-based prospective cohort study of 90,296 Japanese subjects (aged, 45-74 y). Hazard ratios and 95% confidence intervals (CIs) for the highest vs the lowest quintile were estimated from multivariable adjusted Cox proportional hazards regression models. We also conducted subanalyses of subjects with known hepatitis B virus (HBV) or hepatitis C virus (HCV) status, and of subjects who were anti-HCV and/or hepatitis B surface antigen positive. All tests of statistical significance were 2-sided. RESULTS Among all subjects, consumption of n-3 PUFA-rich fish and individual n-3 PUFAs was associated inversely with HCC, in a dose-dependent manner. Hazard ratios for the highest vs lowest quintiles were 0.64 (95% CI, 0.42-0.96) for n-3 PUFA-rich fish, 0.56 (95% CI, 0.36-0.85) for EPA, 0.64 (95% CI, 0.41-0.98) for DPA, and 0.56 (95% CI, 0.35-0.87) for DHA. These inverse associations were similar irrespective of HCV or HBV status. CONCLUSIONS Consumption of n-3 PUFA-rich fish or n-3 PUFAs, particularly EPA, DPA, and DHA, appears to protect against the development of HCC, even among subjects with HBV and/or HCV infection.

Consumption of sodium and salted foods in relation to cancer and cardiovascular disease: the Japan Public Health Center-based Prospective Study.

BACKGROUND Although the influence of salt, per se, on the risk of cancer or cardiovascular disease (CVD) might differ from that of salt-preserved foods, few studies have simultaneously examined the effects of sodium and salted foods on the risk of either cancer or CVD. OBJECTIVE We simultaneously examined associations between sodium and salted food consumption and the risk of cancer and CVD. DESIGN During 1995-1998, a validated food-frequency questionnaire was administered to 77,500 men and women aged 45-74 y. During up to 598,763 person-years of follow-up until the end of 2004, 4476 cases of cancer and 2066 cases of CVD were identified. RESULTS Higher consumption of sodium was associated with a higher risk of CVD but not with the risk of total cancer: multivariate hazard ratios for the highest compared with lowest quintiles of intake were 1.19 (95% CI: 1.01, 1.40; P for trend: 0.06) for CVD and 1.04 (95% CI: 0.93, 1.16; P for trend: 0.63) for total cancer. Higher consumption of salted fish roe was associated with higher risk of total cancer, and higher consumption of cooking and table salt was associated with higher risk of CVD. Similar results were seen for the risk of gastric or colorectal cancer and stroke. CONCLUSIONS Sodium intake as a whole salt equivalent may not increase the risk of cancer but may increase that of CVD. In contrast, salted food intake may increase the risk of cancer. Our findings support the notion that sodium and salted foods have differential influences on the development of cancer and CVD.

Body weight at age 20 years, subsequent weight change and breast cancer risk defined by estrogen and progesterone receptor status--the Japan public health center-based prospective study.

Few prospective studies have investigated the association between BMI at age 20 years (BMI20y) and breast cancer risk with consideration to estrogen/progesterone receptor status (ER/PR). We evaluated the association between BMI20y and ER/PR‐defined breast cancer risk among 41,594 women in the population‐based Japan Public Health Center‐based Prospective Study. Anthropometric factors were assessed using self‐reported questionnaires. Relative risks (RRs) were estimated by Cox proportional hazards regression models. Through to the end of 2006, 452 breast cancer cases were identified. We observed a statistically significant inverse association between BMI20y and breast cancer incidence [multivariable‐adjusted RR for each 5‐unit increment 0.75 (95%CI = 0.61–0.92)], which was not modified by menopausal or recent BMI status. In contrast, recent BMI and subsequent BMI gain were not associated with increased risk among premenopausal women, but were substantially associated with increased risk among postmenopausal women [corresponding RRrecent BMI = 1.31 (95%CI = 1.07–1.59); RRsubsequent BMI gain = 1.32 (95%CI = 1.09–1.60)]. In subanalyses by receptor status (∼50% of cases), the observed inverse association of BMI20y with risk was consistent with the result for ER–PR– [0.49 (95%CI = 0.27–0.88)], while the observed positive associations of BMI gain with postmenopausal breast cancer risk appeared to be confined to ER+PR+ tumors [corresponding RRfor subsequent BMI gain =2.24 (95%CI = 1.50–3.34)]. Low BMI at age 20 years was substantially associated with an increased risk of breast cancer. In contrast, high recent BMI and subsequent BMI gain from age 20 were associated with increased risk of postmenopausal ER+PR+ tumors.

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 ⩾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.

Isoflavone intake and risk of lung cancer: a prospective cohort study in Japan

BACKGROUND Although case-control studies support the idea that soy foods or isoflavone intake is associated with a decreased risk of lung cancer, little evidence is available from prospective cohort studies. Moreover, no prospective study has addressed this association in men. OBJECTIVE We investigated the association between isoflavone intake and lung cancer incidence. DESIGN We conducted a population-based prospective cohort study in 36,177 men and 40,484 women aged 45-74 y with no history of cancer at baseline in 1995-1999. Participants responded to a validated questionnaire, which included 138 food items. We used Cox proportional hazards regression analysis to estimate the hazard ratios (HRs) and 95% CIs of lung cancer incidence according to isoflavone intake, which was estimated by genistein content from soy foods. RESULTS During 11 y (671,864 person-years) of follow-up, we documented 481 male and 178 female lung cancer cases. In men we found an inverse association between isoflavone intake and risk of lung cancer in never smokers (n = 13,051; multivariate HR in the highest compared with the lowest quartile of isoflavone intake: 0.43; 95% CI: 0.21, 0.90; P for trend = 0.024) but not in current or past smokers. A similar, nonsignificant inverse association was seen in never-smoking women (n = 38,211; HR: 0.67; 95% CI: 0.41, 1.10; P for trend = 0.135). We also tested effect modification by smoking status (P for interaction = 0.085 in men and 0.055 in men and women combined). CONCLUSION In a large-scale, population-based, prospective study in Japan, isoflavone intake was associated with a decreased risk of lung cancer in never smokers.

Intake of n-3 and n-6 polyunsaturated fatty acids and development of colorectal cancer by subsite: Japan Public Health Center–based prospective study†

To date, epidemiologic studies investigating intake of n‐3 and n‐6 polyunsaturated fatty acids and risk of colorectal cancer are limited, and results remain inconsistent. This is the first prospective study to show the association by subsite (proximal colon, distal colon, rectum). To clarify the role of n‐3 and n‐6 polyunsaturated fatty acids intake in colon carcinogenesis, we conducted a large, population‐based prospective study, characterized by high fish consumption and a wide range of n‐3 polyunsaturated fatty acids intakes. Subjects were followed from response to a lifestyle questionnaire in 1995–1999 through 2006. During 827,833 person‐years of follow‐up (average 9.3 years), we identified 1,268 new colorectal cancer cases (521 colon and 253 rectal for men; 350 colon and 144 rectal for women). Compared to the lowest quintile, the relative risk and 95% confidence interval of developing cancer among the fifth quintile of marine n‐3 polyunsaturated fatty acids intake were 0.60 and 0.31–1.14, respectively (p for trend = 0.04) in the colon in women and 0.35 and 0.14–0.88 (p for trend = 0.05) and 1.82 and 0.79–4.20 (p for trend = 0.16) in the proximal and distal colon, respectively, in men. For rectal cancer, the dose response for marine n‐3 polyunsaturated fatty acids s was unclear; rather, we observed U‐shaped associations in men and women. We found no evidence that n‐6 polyunsaturated fatty acids increases or the n‐3/n‐6 ratio decreases the risk of colorectal cancer. Our results suggest that intake of marine n‐3 polyunsaturated fatty acids may be inversely related to the risk of cancer in the proximal site of the large bowel.

Dietary cadmium intake and breast cancer risk in Japanese women: a case-control study.

Cadmium, an environmental pollutant, may act like an estrogen and be a potential risk factor for estrogen-dependent diseases such as breast cancer. We examined the hypothesis that higher dietary cadmium intake is associated with risk of overall and hormone receptor-defined breast cancer in Japanese women, a population with a relatively high cadmium intake. The study was conducted under a case-control design in 405 eligible matched pairs from May 2001 to September 2005 at four hospitals in Nagano Prefecture, Japan. Dietary cadmium intake was estimated using a food frequency questionnaire. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer and its hormone-receptor-defined subtypes were calculated by tertile of dietary cadmium intake. We found no significant association between dietary cadmium and risk of total breast cancer in either crude or multivariable-adjusted analysis. Adjusted ORs for tertiles of cadmium intake were 1.00, 1.19, and 1.23 (95% CI, 0.76-2.00; P for trend=0.39) for whole breast cancer. Further, no significant associations were seen across strata of menopausal status, smoking, and diabetes in multivariable-adjusted models except for adjusted OR for continuous cadmium intake in postmenopausal women. A statistically significant association was found for estrogen receptor-positive (ER+) tumors among postmenopausal women (adjusted OR=1.00, 1.16, and 1.94 [95% CI, 1.04-3.63; P for trend=0.032]). Although the present study found no overall association between dietary cadmium intake and breast cancer risk, higher cadmium intake was associated with increased risk of ER+ breast cancer in postmenopausal women, at least at regular intake levels in Japanese women in the general population. Further studies are needed to confirm this association.

Risk factors for epithelial ovarian cancer in Japan - results from the Japan Public Health Center-based Prospective Study cohort.

The aim of this study was to evaluate the risk factors for invasive primary epithelial ovarian cancer among Japanese women. In 1990-1994, 45,748 women aged 40-69 years were enrolled in the Japan Public Health Center-based Prospective Study cohort. Only 86 epithelial ovarian cancer cases were diagnosed during follow-up through 2008, reflecting the low ovarian cancer incidence rates in Japan. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) according to the exposure of interest. The median age at epithelial ovarian cancer diagnosis was 59 years, with a median follow-up before diagnosis of 7.6 years. There were no statistically significant associations for age at menarche or first birth, breastfeeding, use of exogenous hormones, menopausal status at cohort enrollment, height, body mass index, smoking status, second-hand smoke, alcohol consumption, physical activity and family history of cancer in a first-degree relative. The linear decrease in HR associated with each additional birth was 0.75 (95% CI 0.56-0.99). Among women who usually slept >7 h per day, an HR of 0.4 (95% CI 0.2-0.9) emerged compared to those who slept <6 h. This study did not confirm risk factors for epithelial ovarian cancer among Japanese women that have been reported in studies carried out elsewhere. Usual sleep duration of >7 h per day was inversely associated with epithelial ovarian cancer risk, which is a novel finding that needs to be confirmed in other studies.

Seaweed consumption and the risk of thyroid cancer in women: the Japan Public Health Center-based Prospective Study.

Iodine is a suspected risk factor for thyroid cancer. Seaweed accounts for about 80% of Japanese people’s iodine intake. We examined the association between seaweed consumption and the risk of thyroid cancer in Japanese women. Women participating in the Japan Public Health Center-based Prospective Study (n=52 679; age: 40–69 years) were followed up for a mean of 14.5 years; 134 new thyroid cancer cases, including 113 papillary carcinoma cases, were identified. Seaweed consumption was assessed using a food-frequency questionnaire and divided into three categories: 2 days/week or less (reference); 3–4 days/week; and almost daily. The Cox proportional hazards model was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Seaweed consumption was clearly associated with an increased risk of papillary carcinoma (HR for almost daily consumption compared with 2 days/week or less=1.71; 95% CI: 1.01–2.90; trend P=0.04). After stratification for menopausal status, an increased risk was observed in postmenopausal women (papillary carcinoma HR for almost daily consumption compared with 2 days/week or less=3.81, 95% CI: 1.67–8.68; trend P<0.01), but not in premenopausal women (HR=0.91, 95% CI: 0.44–1.91; trend P=0.76). This study identified a positive association between seaweed consumption and the risk of thyroid cancer (especially for papillary carcinoma) in postmenopausal women.