Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Height, body mass index, physical activity, and risk of colorectal cancer in relation to expression of insulin receptor: The Japan Public Health Center-based Prospective Study.

To ascertain the involvement of insulin receptors (IRs) in colorectal carcinogenesis, we investigated the association of height, body mass index (BMI), and physical activity with colorectal cancer (CRC) and two subtypes of CRC according to the expression level of IR. We utilized data from a large-scale, population-based prospective cohort study of 18,158 middle-aged and elderly subjects in Akita and Okinawa, Japan. In the statistical analysis, we used the Cox proportional hazards model and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subtypes as defined by immunohistochemistry of IRß, a transmembrane subunit of IR. In the IRß-defined subtypes, height showed no apparent association with the risk of IRß-positive CRC. In contrast, a multivariable HR of IRß-positive CRC was 1.77 (95% CI = 1.04-3.03) with a BMI of ≥30.0 kg/m2 (i.e., obesity), compared to a BMI of <25.0 kg/m2. Further, an increase in physical activity was significantly associated with decreased risk of IRß-positive CRC (multivariable HR per 5 METs-hour/day = 0.93, 95% CI = 0.88-0.99). Meanwhile, we found no significant association between any exposure and IRß-negative CRC. Likewise, heterogeneity between the two subtypes of CRC was not statistically significant. These findings imply that obesity and physical activity exert promoting and suppressing effects on the development of CRC expressing IRs, respectively.

Plasma Albumin, Bilirubin, and Uric Acid and the Subsequent Risk of Cancer: A Case-Cohort Study in the Japan Public Health Center-based Prospective Study.

Several epidemiological studies have investigated the circulating levels of albumin, bilirubin, and uric acid (UA) in relation to cancer risk; however, they have provided equivocal evidence. In this prospective case-cohort study, we aimed to explore the association of plasma albumin, bilirubin, and UA levels with cancer incidence. We measured the plasma levels of albumin, bilirubin, and UA and investigated their association with cancer incidence in 3,584 cases and 4,270 randomly selected participants with a median follow-up of 15.8 years. The adjusted hazard ratios (HR) and 95% confidence intervals (CI) of total cancer for the highest (Q4) versus lowest quartile (Q1) was 0.77 (95% CI: 0.67-0.90, P for trend: <0.001) for albumin. This association was attenuated after excluding liver cancer cases with lower plasma albumin levels. Plasma bilirubin levels were positively related to liver cancer but inversely to total cancer after excluding liver cancer with adjusted HR Q4 vs. Q1 of 0.86 (95% CI: 0.74-0.99, P for trend = 0.015). Plasma UA levels were not dose-responsively associated with total cancer risk. Higher plasma bilirubin levels were associated with a decreased risk of total cancer after excluding liver cancer, which is likely attributed to the antioxidant properties of bilirubin.

Association of depressive symptoms with incident fractures: the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT).

This 5-year longitudinal study investigated the relationship between depressive symptoms and fracture risk in a large Japanese cohort. Depressive symptoms were a significant risk factor for hip fractures in women. PURPOSE: A relationship between depressive symptoms and fractures has not been clearly demonstrated. We aimed to investigate the relationship between depressive symptoms and 5-year fracture risk in the Japan Public Health Center-based Prospective Study for the Next Generation. METHODS: From 2011 to 2016, 114,092 participants were enrolled, and a follow-up survey was conducted 5 years later. We analyzed 30,552 men and 38,063 women aged 40-74 years who had no past fractures at baseline. Presence of depressive symptoms was defined as a modified 11-item Center for Epidemiological Studies Depression Scale score of 8 or higher, a history of depression, or use of antidepressants. Subjects were asked to report vertebral, upper limb, and/or hip fractures, except for traffic or work accidents, that occurred during the follow-up period. The adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for fracture were analyzed via logistic regression analysis to evaluate the relationship between depressive symptoms and fracture. RESULTS: Women with depressive symptoms demonstrated a high AOR for hip fractures (AOR: 2.78, 95% CI: 1.30 - 5.92); this result was consistent in post menopause women. In men, this association was not found for any age group or any type of fracture. CONCLUSIONS: Depressive symptoms in women may increase the risk of hip fractures. Further studies are required to explore this relationship in more detail.

Intake of Sugar and Food Sources of Sugar and Colorectal Cancer Risk in the Multiethnic Cohort Study.

BACKGROUND: The influence of sugar intake on the risk of colorectal cancer (CRC) remains controversial, and there is a need to investigate the heterogeneity of effects among racial and ethnic groups. OBJECTIVES: To examine the association of intake of simple sugars and their food sources with CRC risk according to race/ethnicity in a multiethnic cohort study. METHODS: We analyzed data from 192,651 participants who participated in the Multiethnic Cohort Study comprising African American, Japanese American, Latino, Native Hawaiian, and White older adults living in Hawaii and California with an average follow-up of 19 y. Intakes of total and specific types of sugars and sugary foods were estimated from a quantitative food frequency questionnaire completed by the participants in 1993-1996. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC risk according to quintiles (Q) of sugar and food intakes using Cox models adjusted for potential confounders. RESULTS: As of December 2017, 4403 incident CRC cases were identified. Among all participants, multivariable-adjusted CRC HRs for Q2, Q3, Q4, and Q5 compared with Q1 for total sugars were 1.03 (95% CI: 0.94, 1.13), 1.05 (95% CI: 0.96, 1.16), 1.12 (95% CI: 1.01, 1.24), and 1.13 (95% CI: 1.01, 1.27), respectively. A similar positive association was observed for total fructose, glucose, fructose, and maltose but not for added sugars and sugary foods. The increased risk appeared to be limited to colon cancer and to be strongest among younger participants (i.e., 45-54 y at baseline); an association with CRC was observed for sugar-sweetened beverages in the latter group. Among racial and ethnic groups, increased risk of CRC was most apparent in Latinos. CONCLUSIONS: In this diverse cohort, intakes of total sugar, total fructose, glucose, fructose, and maltose were associated with an increased risk of CRC, and the association was strongest for colon cancer, younger participants, and Latinos.

Sex difference in the association of dietary fiber intake with visceral fat volume in Japanese adults.

PURPOSE: Dietary fiber is a possible nutritional component which aids in the prevention of visceral fat accumulation. We examined the association between dietary fiber intake and visceral fat volume (VFV) by sex, and further analysed the association by major food sources of dietary fiber. METHODS: In this cross-sectional study, we measured VFV in 2779 Japanese (1564 men and 1215 women) aged 40-89 who underwent positron emission tomography/computed tomography for cancer screening between 2004 and 2005. Dietary fiber intake was calculated based on a validated semi-quantitative food frequency questionnaire. The association between dietary fiber intake and VFV was investigated using multivariate linear regression models after adjustment for potential confounders. RESULTS: Total, soluble, and insoluble fiber intakes were inversely associated with VFV in men (Q1: 3740 cm3, Q4: 3517 cm3, Ptrend: 0.0006 for total fiber), but not in women (Q1: 2207 cm3, Q4: 2193 cm3,Ptrend: 0.88 for total fiber). Statistically significant sex difference was observed (Pinteraction = 0.001 for total fiber). Subgroup analyses by major food sources revealed that dietary fiber intakes from beans, vegetables and fruits showed an inverse association with VFV in men, while cereal fiber intake showed a tendency toward a positive association in both sexes (Q1: 3520 cm3, Q4: 3671 cm3, Ptrend: 0.05 in men, Q1: 2147 cm3, Q4: 2227 cm3, Ptrend: 0.10 in women). CONCLUSION: We observed a sex-specific association between dietary fiber intake and VFV in Japanese adults. This study suggests that efforts against visceral fat accumulation should take account of the source of dietary fiber.

Association between fish and shellfish consumption, n-3 polyunsaturated fatty acids, and gastric cancer risk: the Japan Public Health Center-based Prospective Study.

PURPOSE: Fish and shellfish consumption is suggested to be a cancer-protective factor. However, studies investigating this association for gastric cancer, especially considering Helicobacter pylori (H. pylori) and atrophic gastritis (AG), are limited. We investigated gastric cancer risk associated with fish, shellfish, and n-3 polyunsaturated fatty acids (n-3 PUFAs) consumption among Japanese adults. METHODS: 90,504 subjects enrolled in the Japan Public Health Center-based Prospective Study (JPHC Study) were followed until December 2013. Dietary intake data were collected using a food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for gastric cancer risk associated with fish and shellfish consumption and marine n-3 PUFAs (sum of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA)) using Cox proportional hazards models. Among those with avaliable data, we conducted a subgroup analysis taking H. pylori infection and AG status  into consideration. RESULTS: There were 2,701 gastric cancer cases during an average of 15 years of follow-up. We observed an increased gastric cancer risk for salted fish consumption for men [HR for fifth quintile versus first quintile 1.43 (95% CI 1.18-1.75)] and for women [HR 1.33 (95% CI 1.00-1.77)]. We observed a weak risk reduction trend for women as the intake of marine n-3 PUFAs increased (p-trend:0.07). When we included H. pylori infection and atrophic gastritis status in the analysis, the associations diminished. CONCLUSION: Our results suggest that salted fish increases gastric cancer risk for men and women, while marine n-3 PUFAs marginally decreases this risk among women in Japan.

Importance of circulating leptin and adiponectin in the causal pathways between obesity and the development of colorectal cancer in Japanese men.

BACKGROUND: The mechanistic associations between obesity and risk of colorectal cancer (CRC) remain unclear. Here, using body mass index (BMI) as an obesity indicator, we decomposed the total effects of obesity on the risk of CRC into: (1) direct effects, which are possibly mediated by unmeasured or currently unknown factors; (2) indirect effects mediated by circulating leptin and adiponectin; and (3) indirect effects that are not mediated by circulating leptin and adiponectin but by hyperinsulinemia and chronic inflammation (assessed via circulating connecting peptide and C-reactive protein, respectively). METHODS: We adopted a causal mediation framework, using data from a large prospective cohort study of 44,271 Japanese men. RESULTS: BMI was not associated with the risk of CRC due to direct and indirect effects that were not mediated by circulating leptin and adiponectin. By contrast, individuals with BMIs of 25.0-27.4 kg/m2 (risk ratio, 1.29; 95% confidence interval, 0.98-1.69) and ≥27.5 kg/m2 (risk ratio, 1.28; 95% confidence interval, 0.98-1.68) had a higher risk of CRC due to indirect effects of circulating leptin and adiponectin. CONCLUSIONS: Our mediation analyses suggest that the association between BMI and CRC risk may be largely mediated by a pathway involving circulating leptin and adiponectin.

Dietary Consumption of Antioxidant Vitamins in Relation to Prostate Cancer Risk in Japanese Men: The Japan Public Health Center-based Prospective Study.

BACKGROUND: Many epidemiological studies have investigated dietary intake of antioxidant vitamins in relation to prostate cancer risk in Western countries, but the results are inconsistent. However, few studies have reported this relationship in Asian countries. METHODS: We investigated the association between intake of vitamins, including lycopene, α-carotene, ß-carotene, vitamin C, vitamin E, with prostate cancer risk in the Japan Public Health Center-based Prospective (JPHC) study. 40,720 men without history of cancer finished the food frequency questionnaire (FFQ) and were included in the study. Hazard ratios (HRs) and 95% confidence intervals (CIs) of prostate cancer risk were calculated according to the quintiles of energy-adjusted intake of vitamins using Cox models. RESULTS: After an average of 15.2 years (617,599 person-years in total) of follow-up, 1,386 cases of prostate cancer were identified, including 944 localized cases and 340 advanced cases. No associations were observed in consumption of antioxidant vitamins, including α-carotene, ß-carotene, vitamin C, and vitamin E, and prostate cancer risk. Although higher lycopene intake was associated with increased risk of prostate cancer (highest vs lowest quintile, HR 1.24; 95% CI, 1.04-1.47; P for trend = 0.01), there was a null association of lycopene intake with risk of prostate cancer detected by subjective symptoms (HR 1.12; 95% CI, 0.79-1.58; P for trend = 0.11). CONCLUSION: Our study suggested no association between antioxidant intake of vitamins and prostate cancer risk.

GWAS meta-analysis of kidney function traits in Japanese populations.

BACKGROUND: Genetic epidemiological evidence for the kidney function traits in East Asian population including Japanese remain still relatively unclarified. Especially, the number of GWASs for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. METHODS: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). RESULTS: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; p < 5×10-8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; p < 5×10-8), of which one locus (more than 1Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. CONCLUSIONS: The present GWAS meta-analysis of largest genome cohort studies in Japanese provided some original genomic loci associated with kidney function in Japanese, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Long-term outcomes of spine surgery in dialysis patients, focusing on activities of daily living, life expectancy, and the risk factors for postoperative mortality.

BACKGROUND: Because of the high incidence of major perioperative adverse events, spine surgery in dialysis patients should be recommended carefully after consideration of its risks and benefits. However, the benefits of spine surgery in dialysis patients remain unclear because of the lack of long-term outcomes. The purpose of this study is to elucidate the long-term outcomes of spine surgery in dialysis patients, focusing on activities of daily living (ADLs), life expectancy, and risk factors for postoperative mortality. METHODS: Data for 65 dialysis patients who underwent spine surgery at our institution and were followed up for a mean duration of 6.2 years were retrospectively reviewed. ADLs, number of surgeries, and survival times were recorded. The postoperative survival rate was calculated using the Kaplan-Meier method, and risk factors for postoperative mortality were investigated using a generalized Wilcoxon test and multivariate Cox proportional-hazards model. RESULTS: Compared with preoperative ADLs, ADLs significantly improved at discharge after surgery and at the final follow-up. However, 16 of the 65 patients (24.6%) underwent multiple surgeries, and 34 (52.3%) died during the follow-up period. Kaplan-Meier analysis revealed that the survival rate after spine surgery was 95.4% at 1 year, 86.2% at 3 years, 69.6% at 5 years, 59.7% at 7 years, and 28.7% at 10 years, and the overall median survival time was 99 months. Multivariate Cox regression analysis showed that a dialysis period of ≥10 years was a significant risk factor. CONCLUSIONS: Spine surgery in dialysis patients improved and maintained ADLs in the long term and did not shorten life expectancy. However, dialysis patients undergoing spine surgery require multiple surgeries more frequently, and a dialysis period of ≥10 years is a significant risk factor for postoperative mortality.

Smoking and risk of colorectal cancer according to KRAS and BRAF mutation status in a Japanese prospective Study.

Although smoking is a major modifiable risk factor for many types of cancer, evidence for colorectal cancer is equivocal in Asian populations. Recent Western studies have proposed that the association between smoking and colorectal cancer is restricted to specific tumor molecular subtypes. However, no studies have evaluated the association according to tumor molecular subtypes in Asian populations. In a Japanese prospective population-based cohort study of 18 773 participants, we collected tumor tissues from incident colorectal cancer cases and evaluated KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B) mutation status using target sequencing. Multivariable-adjusted Cox proportional hazard model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of smoking with the risk of overall colorectal cancer and its subtypes defined by KRAS and BRAF mutation status. Among 339 cases, KRAS and BRAF mutations were identified in 164 (48.4%) and 16 (4.7%) cases, respectively. The multivariable-adjusted HR for ever smoking compared with never smoking was 1.24 [95% CI: 0.93-1.66], 1.75 [1.14-2.68], 0.87 [0.59-1.29], 1.24 [0.93-1.67] and 1.22 [0.38-3.93] for overall, KRAS wild-type, KRAS-mutated, BRAF wild-type and BRAF-mutated colorectal cancer, respectively. The statistically significant heterogeneity was indicated between KRAS mutation status (Pheterogeneity = 0.01) but not between BRAF mutation status. This study is the first to demonstrate that smokers have an approximately 2-fold higher risk of KRAS wild-type colorectal cancer than never smokers in an Asian population. Our findings support that smoking is a risk factor for colorectal cancer, especially for its subtype without KRAS mutations, in Asian populations.

Sugar intake and colorectal cancer risk: A prospective Japanese cohort study.

The influence of sugar consumption on the risk of colorectal cancer (CRC) remains controversial. Prospective cohort studies focusing on total and specific types of sugar intake among the Asian population who have different patterns of sugar intake sources than American and European populations are scarce. We intended to examine the association of sugar intake with CRC risk among middle-aged adults in a Japanese large-scale population-based cohort study. The participants (42,405 men and 48,600 women) who were 45-74 years old and answered the questionnaire in 1995-1999 in the Japan Public Health Center-based Prospective Study were followed up until December 2013. Total sugars, total fructose, and specific types of sugar intake were estimated using a validated 147-item food frequency questionnaire and divided into quintiles (Q1-Q5). We used Cox proportional hazard regression models adjusted for potential confounders to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During the follow-up, 2118 CRC cases (1226 men and 892 women) were identified. We did not observe any clear association between all types of sugar intake and an increased risk of CRC. Analyses by tumor sites yielded a positive association of total sugar consumption with rectal cancer in women (1.75 [1.07-2.87] for Q1 vs. Q5; p linear trend  = 0.03), but no statistically significant trend was detected among men. Sugar intake was not associated with CRC risk in middle-aged Japanese adults. However, for rectal cancer, the probability of an increased risk among women with a higher total sugar intake cannot be excluded.

Development and validation of genome-wide polygenic risk scores for predicting breast cancer incidence in Japanese females: a population-based case-cohort study.

PURPOSE: This study aimed to develop an ancestry-specific polygenic risk scores (PRSs) for the prediction of breast cancer events in Japanese females and validate it in a longitudinal cohort study. METHODS: Using publicly available summary statistics of female breast cancer genome-wide association study (GWAS) of Japanese and European ancestries, we, respectively, developed 31 candidate genome-wide PRSs using pruning and thresholding (P + T) and LDpred methods with varying parameters. Among the candidate PRS models, the best model was selected using a case-cohort dataset (63 breast cancer cases and 2213 sub-cohorts of Japanese females during a median follow-up of 11.9 years) according to the maximal predictive ability by Harrell's C-statistics. The best-performing PRS for each derivation GWAS was evaluated in another independent case-cohort dataset (260 breast cancer cases and 7845 sub-cohorts of Japanese females during a median follow-up of 16.9 years). RESULTS: For the best PRS model involving 46,861 single nucleotide polymorphisms (SNPs; P + T method with PT = 0.05 and R2 = 0.2) derived from Japanese-ancestry GWAS, the Harrell's C-statistic was 0.598 ± 0.018 in the evaluation dataset. The age-adjusted hazard ratio for breast cancer in females with the highest PRS quintile compared with those in the lowest PRS quintile was 2.47 (95% confidence intervals, 1.64-3.70). The PRS constructed using Japanese-ancestry GWAS demonstrated better predictive performance for breast cancer in Japanese females than that using European-ancestry GWAS (Harrell's C-statistics 0.598 versus 0.586). CONCLUSION: This study developed a breast cancer PRS for Japanese females and demonstrated the usefulness of the PRS for breast cancer risk stratification.

Association of chronic kidney disease with total and site-specific cancer incidence in participants of the Japan Public Health Center-based Prospective Study.

BACKGROUND: Although studies have found an association between chronic kidney disease (CKD) and cancer incidence, the results are inconsistent. METHODS: This study included participants in the Japan Public Health Center-based Prospective Study who had data on serum creatinine measurements. We assessed the association between estimated glomerular filtration rate (eGFR) and the risk of total and site-specific cancer incidence using a systematic survey in Japan. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for participant demographics and lifestyle factors. RESULTS: A total of 21 978 participants who met the inclusion criteria were followed up for a mean period of 12.9 years, during which a total of 2997 incident cancer cases were reported. In the multivariable adjusted models, an eGFR of <45 mL/min/1.73 m2 was not significantly associated with total cancer incidence (adjusted HR 1.22, 95% CI 0.94-1.60), compared with an eGFR of 60-89 mL/min/1.73 m2 (reference). The HR among those with eGFRs of ≥90 mL/min/1.73 m2 was 1.10 (95% CI 1.00-1.22). CONCLUSIONS: In this large prospective study, a low eGFR was not significantly associated with an increased risk of total cancer incidence in patients with CKD, which may be partly due to an underpowered sample size. This finding may be due to the many shared risk factors between CKD and cancer.

Dietary sodium sources according to four 3-d weighed food records and their association with multiple 24-h urinary excretions among middle-aged and elderly Japanese participants in rural areas.

Reducing Na intake is an urgent global challenge, especially in East Asia and high-income Asia-Pacific regions. However, the sources of Na and their effects on urinary Na excretion have not been fully studied. We sought to clarify these sources and their association with urinary Na excretion. We examined four 3-d weighed food records and five 24-h urinary collections from each of 253 participants in Japan, aged 35-80 years, between 2012 and 2013. We compared the levels of Na according to four categories: foods contributing to discretionary or non-discretionary Na intake, the situation in which dishes were cooked and consumed, food groups and types of cuisine. We also conducted regression analysis in which 24-h urinary Na excretion was a dependent variable and the amounts of food intake in the four categories were independent variables. Levels of Na were the highest in discretionary intake (60·6 %) and in home-prepared dishes (84·0 %). Of the food groups, miso soup showed the highest percentage contribution to Na intake (13·3 %) after seasonings such as soya sauce. In the regression analysis, the standardised coefficient for foods of non-discretionary Na sources was larger than that for discretionary sources, whereas that for home-prepared dishes was consistent with the levels of Na in those foods. Pickled products, followed by fresh fish and shellfish, miso soup and rice, were associated with high urinary Na excretion. Thus, discretionary foods (such as miso soup) contribute the most to Na consumption, although non-discretionary intake (such as pickled vegetables) may influence urinary Na excretion.

Associations between dairy intake and mortality due to all-cause and cardiovascular disease: the Japan Public Health Center-based prospective study.

BACKGROUND: Some studies have investigated the relation between dairy products and mortality, but with inconsistent results. OBJECTIVE: We examined the association between the consumption of dairy products and the risk of all-cause, cancer-related, and cardiovascular disease (CVD)-related mortality. METHODS: From the Japan Public Health Center-based Prospective (JPHC) study, 43,117 males and 50,193 females with no history of cancer or CVD finished the food frequency questionnaire (FFQ) and were included in the study. Intake of dairy products was assessed using the FFQ and adjusted for total energy by using the residual method. We used multivariate Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for mortality risk in males and females. RESULTS: 14,211 deaths in males and 9547 deaths in females from all causes were identified during an average follow-up of 19.3 years. For males, total dairy consumption was nonlinearly and significantly associated with lower risk of mortality from all causes [the third quartile, HR = 0.87 (0.83, 0.91), the fourth quartile, HR = 0.89 (0.85, 0.94), P for nonlinearity < 0.001] and CVD [the third quartile, HR = 0.77 (0.70, 0.85), the fourth quartile, HR = 0.78 (0.70, 0.86), P for nonlinearity < 0.001]. Milk and fermented milk intake were inversely associated with all-cause and CVD-related mortality in males. Cheese consumption was inversely associated with CVD-related mortality among males. There was no association between total dairy intake and mortality risk among females. CONCLUSION: For Japanese people, consumption of dairy products was associated with a decreased risk of mortality from all-cause and cardiovascular diseases among males.

Isoflavone and soy food intake and risk of lung cancer in never smokers: report from prospective studies in Japan and China.

PURPOSE: Evidence from several cohorts has suggested that a higher intake of isoflavone is associated with lower risk of lung cancer in never smokers, but the association has not been investigated by histologic type of lung cancer. Adenocarcinoma is a common histologic type found in never smokers. We hypothesized that a higher intake of isoflavone is associated with a lower risk of lung adenocarcinoma among never smokers. Here, we examined the associations of isoflavone and soy food intake with lung cancer and its histologic types in never smokers. METHODS: We performed a pooled analysis using data from the Japan Public Health Center-based Prospective Study, Shanghai Women's Health Study and Shanghai Men's Study with 147,296 never smokers aged 40-74 years with no history of cancer. During 1,990,040 person-years of follow-up, 1247 lung cancer cases were documented. Dietary isoflavone and soy food intake were assessed using a food-frequency questionnaire. Multivariable Cox proportional hazards models assessed the associations between isoflavone and soy intake with incidence of lung cancer by histologic type. RESULTS: A higher intake of dietary isoflavone and soy food were associated with reduced risk of lung adenocarcinoma. The multivariable hazard ratios (HRs) (95% CI) of risk of lung adenocarcinoma for the highest versus lowest intakes of isoflavone and soy food were 0.74 (0.60-0.92) and 0.78 (0.63-0.96), respectively. The multivariable HRs of risk of lung adenocarcinoma associated with each 10 mg/day increase in isoflavone and each 50 g/day increase in soy food intake were 0.81 (0.70-0.94) and 0.84 (0.73-0.96), respectively. CONCLUSION: Higher intake of isoflavone and soy food was associated with lower risk of lung adenocarcinoma in never smokers.

Alcohol consumption from midlife and risk of disabling dementia in a large population-based cohort study in Japan.

OBJECTIVES: The association between alcohol consumption and dementia in Japanese is poorly understood, and use of single-point alcohol assessment may cause measurement error. We explored this association in Japanese using repeated alcohol assessments. METHODS: Participants in the Japan Public Health Center-based Prospective Study (JPHC Study) since 1990 and who were alive in 2006 were followed from 2006 until 2016 for dementia ascertainment. Disabling dementia was identified through long-term care insurance records. Alcohol consumption was assessed at the 5-year questionnaire survey (1995-1999) and drinking patterns were assessed on repeated follow-up (2000-2003). We performed Cox proportional hazards models with age as the time-scale with adjustment for various lifestyle factors and medical history using light consumption (<75 g ethanol/week, hereinafter "g") as reference. Analysis considering death as a competing risk was also conducted. RESULTS: Among 42,870 participants aged 54-84 years, 4802 cases of disabling dementia were newly diagnosed. Average years from alcohol assessment until dementia incidence was 14.9 years. Non-drinkers and regular drinkers with ≥450 g at 5 years had adjusted HRs (95% CI) of 1.29 (1.12-1.47) and 1.34 (1.12-1.60). Patterns of long-term abstinence, former drinking, and regular heavy weekly consumption of ≥450 g showed increased adjusted HRs of 1.61 (1.28-2.03), 2.54 (1.93-3.35), and 1.96 (1.49-2.59), respectively. Competing risk analysis yielded similar results. CONCLUSIONS: In Japanese, non-drinking and regular weekly consumption of ≥450 g from midlife were associated with high risk of disabling dementia compared with light drinking.

Exploratory Research on Determinants of Place of Death in a Large-scale Cohort Study: The JPHC Study.

BACKGROUND: The place of death and related factor, such as diseases, symptoms, family burden, and cost, has been examined, but social background and lifestyle were not considered in most studies. Here, we assessed factors that are associated with the place of death using the largest cohort study in Japan. METHODS: A total of 17,781 deaths from the cohort study were assessed. The study database was created from the Japan Public Health Center-based Prospective Study (JPHC Study), in which demographic data were collected from Japanese Vital Statistics. Adjusted odds ratios for home death were calculated using logistic regression. RESULTS: Multivariate analysis adjusted for various factors showed that unmarried status (odds ratio [OR] 2.4; 95% confidence interval [CI], 2.0-2.9), unemployed male (OR 1.3; 95% CI, 1.1-1.5), and high drinking level in male (OR 1.3; 95% CI, 1.1-1.6) were associated with home death. Regarding the cause of death, cardiovascular disease (OR 3.3; 95% CI, 2.9-3.8), cerebrovascular disease (OR 1.9; 95% CI, 1.6-2.2), and external factors (OR 4.1; 95% CI, 3.5-4.8) were significantly associated with home death, compared with cancer. The risk of death at home was significantly higher among unmarried subjects stratified by cause of death (cardiovascular disease: OR 3.2; 95% CI, 2.2-4.7; cerebrovascular disease: OR :5.1; 95% CI, 2.9-9.1; respiratory disease: OR 3.4; 95% CI, 1.6-7.6; and external factors: OR 2.3; 95% CI, 1.4-3.7), but for cancer, the risk of death at home tended to be higher among married participants. CONCLUSION: This study found that various factors are associated with home death using the largest cohort study in Japan. There is a high possibility of home deaths in people with fewer social connections and in those with diseases leading to sudden death.