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In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.Colorectal cancer stages are associated with distinct microbial and metabolomic profiles that could shed light on cancer progression.

Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel ( N  = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants ( SLC27A3 and CYP26B1 ; P SKAT-O  < 2.5 × 10 −6 ). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations. Thousands of genetic loci are known to associate with human height, but these are mainly based on studies in European ancestry populations. Here, Akiyama et al. construct a genotype reference panel for the Japanese population followed by GWAS and report 573 height associated variants in 191,787 Japanese.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci ( P  < 9.58 × 10 −9 ). East Asian–specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations. Genome-wide analysis in 212,453 Japanese individuals identifies loci associated with 42 diseases. Comparative analysis with European populations identifies East Asian–specific associations.

Background: Few cohort studies have used multiple surveys of screening attendance to simultaneously evaluate the effectiveness of fecal occult blood test (FOBT) and colonoscopy.Methods: We analyzed data of 30,381 middle-aged Japanese adults from a population-based prospective cohort study. Information on FOBT and colonoscopy was obtained from three questionnaire surveys (every 5 years). We classified the subjects into three groups: the FOBT (15,649 subjects), screening colonoscopy (2,407 subjects), and unscreened (12,325 subjects) groups. We used the unscreened group as the reference group to compare the mortality and incidence of colorectal cancer (CRC).Results: During the 14-year follow-up, 64, 12, and 104 CRC deaths were identified in the FOBT, screening colonoscopy, and unscreened groups, respectively. The risk of CRC death reduced with increasing the number of FOBTs (P for trend = 0.02) and was reduced by 44% in the subjects screened twice or thrice using FOBT (hazard ratio [HR] 0.56; 95% confidence interval [CI], 0.33–0.94). Significant decreases were seen for the incidence of CRC but not seen for the incidence of non-advanced CRC in the FOBT group. Concerning the screening colonoscopy, subjects screened at the start of follow-up showed a 69% reduced risk of CRC death (HR 0.31; 95% CI, 0.10–0.9996). Significant decreases were also seen for the incidence of CRC and non-advanced CRC in the subjects screened at the start of follow-up.Conclusion: FOBT, depending on the number of FOBTs, and colonoscopy, depending on recency, reduced the risk of death due to CRC and the incidence of CRC.

Purpose The present study aimed to examine the association between adherence to the Japanese diet and the subsequent risk of all-cause and cause-specific mortality using a large-scale cohort from settings all over Japan. Methods We analyzed data from a cohort study of 92,969 Japanese adults aged 45–74 years, covering 11 public health center areas nationwide. We collected dietary information using a validated 147-item food frequency questionnaire. Adherence to the Japanese diet consisting of eight components (high intake of rice, miso soup, seaweeds, pickles, green and yellow vegetables, fish, and green tea; low intake of beef and pork) was assessed using 8-item Japanese Diet Index (JDI8) score, with scores ranging from 0 to 8. The Cox proportional hazards model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for all-cause and cause-specific mortality. Results During a median follow-up of 18.9 years, we documented 20,596 deaths. A higher JDI8 score was significantly associated with a lower risk for all-cause and cardiovascular disease (CVD) mortality. The multivariable-adjusted HR of all-cause and CVD mortality for the highest JDI8 score group (score of 6–8) versus the lowest JDI8 score group (score of 0–2) were 0.86 (95% CI 0.81–0.90, P trend < 0.001), and 0.89 (95% CI 0.80–0.99, P trend = 0.007), respectively. Conclusions Adhering to the Japanese diet, as assessed by the JDI8, was associated with a decreased risk of all-cause and CVD mortality among adults living in multiple areas across Japan.

Yoichiro Kamatani and colleagues perform a genome-wide association study (GWAS) for body mass index using data from 173,430 Japanese individuals. They find 85 significant loci, 51 of which are novel, and use trans-ancestral meta-analysis of GWAS from European samples to identify 61 additional new loci. Obesity is a risk factor for a wide variety of health problems. In a genome-wide association study (GWAS) of body mass index (BMI) in Japanese people ( n = 173,430), we found 85 loci significantly associated with obesity ( P < 5.0 × 10 −8 ), of which 51 were previously unknown. We conducted trans-ancestral meta-analyses by integrating these results with the results from a GWAS of Europeans and identified 61 additional new loci. In total, this study identifies 112 novel loci, doubling the number of previously known BMI-associated loci. By annotating associated variants with cell-type-specific regulatory marks, we found enrichment of variants in CD19 + cells. We also found significant genetic correlations between BMI and lymphocyte count ( P = 6.46 × 10 −5 , r g = 0.18) and between BMI and multiple complex diseases. These findings provide genetic evidence that lymphocytes are relevant to body weight regulation and offer insights into the pathogenesis of obesity.

Epidemiological evidence on the effects of a long‐term low‐carbohydrate diet (LCD) on cancer incidence remains sparse. We investigate the association between LCD and the risk of overall and specific cancer site incidence in a Japanese population‐based prospective cohort study among 90 171 participants aged 45‐74. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a median 17.0 y of follow‐up, we identified 15 203 cancer cases. A higher overall LCD score was associated with increased overall cancer risk (HR = 1.08 [CI: 1.02‐1.14], P‐trend = .012), while it was associated with decreased gastric cancer (GC) risk (0.81 [0.71‐0.93], P‐trend = .006). A higher animal‐based LCD score was associated with higher risk of overall cancer (1.08 [1.02‐1.14], P‐trend = .003), colorectal cancer (CRC) (1.11 [0.98‐1.25], P‐trend = .018), rectal cancer (RC) (1.24 [1.00‐1.54], P‐trend = .025), lung cancer (LC) (1.16 [1.00‐1.34], P‐trend = .042), and lower risk of GC (0.90 [0.79‐1.01], P‐trend = .033). Furthermore, we found that plant‐based LCD score was related to lower GC incidence (0.87 [0.77‐0.99], P‐trend = .031). Additionally, adjusted for plant fat intake amplified the adverse associations (overall cancer: 1.08 [1.02‐1.14] vs. 1.11 [1.05‐1.18]; CRC: 1.08 [0.95‐1.22] vs. 1.13 [0.99‐1.30]; LC: 1.14 [0.98‐1.33] vs. 1.19 [1.01‐1.41]). We conclude that LCD enriching with animal products was associated with increased overall cancer, CRC, and LC incidence. These adverse associations could be attenuated by plant fat consumption. LCD reduces the risk of developing GC. Long‐term adherence to LCD without paying attention to the balance between animal and plant food source consumption might cause adverse overall cancer incidence consequences. Epidemiological evidence on the effects of a long‐term low‐carbohydrate diet (LCD) on cancer incidence remains sparse. In this cohort study, the authors found that a higher animal‐based LCD score was associated with a higher risk of overall cancer, colorectal cancer, lung cancer, and a lower risk of gastric cancer (GC). A plant‐based LCD score was associated with decreased GC incidence.

Upper gastrointestinal endoscopy for gastric cancer screening has been implemented in Japan. However, its effectiveness for gastric cancer prevention has not been fully studied. We aimed to investigate the effectiveness of endoscopic screening to reduce mortality from gastric cancer. In a large prospective population‐based cohort study including 80,272 participants, we compared the risk of mortality and incidence of gastric cancer among participants who underwent endoscopic or radiographic screening compared with those who did not undergo any screening using multivariable Cox proportional hazards models. In the 1,023,364 person‐year observation period (median; 13.0 years), 1977 cases of gastric cancer were diagnosed, and 783 patients with gastric cancer died. In the endoscopic screening group, the mortality from gastric cancer and incidence of advanced gastric cancer were reduced by 61% (hazard ratio [HR] = 0.39 [95% CI: 0.30–0.51]) and 22% (HR = 0.78 [95% CI: 0.67–0.90]), respectively. The radiographic screening reduced the mortality from gastric cancer (HR = 0.63 [95% CI: 0.54–0.73]), but its effectiveness was lower than that of endoscopic screening. In conclusion, endoscopic screening reduced the incidence of advanced gastric cancer and mortality from gastric cancer in the Japanese population. In this Japanese prospective population‐based cohort study, endoscopic screening reduced the incidence of advanced gastric cancer by 22% and mortality from gastric cancer by 61% compared with no screening. The effectiveness of endoscopic screening on reducing gastric cancer mortality was greater than that of radiographic screening. The results provide a rationale for promoting endoscopic screening for gastric cancer, which has a high mortality rate and significant public health impact in Japan.

Background: Lifestyle and life-environment factors have undergone drastic changes in Japan over the last few decades. Further, many molecular epidemiologic studies have reported that genetic, epigenetic, and other biomarker information may be useful in predicting individual disease risk. Methods: The Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT) was launched in 2011 to identify risk factors for lifestyle-related disease, elucidate factors that extend healthy life expectancy, and contribute toward personalized healthcare based on our more than 20 years’ experience with the JPHC Study. From 2011 through 2016, a baseline survey was conducted at 16 municipalities in seven prefectures across the country. A self-administered questionnaire was distributed to all registered residents aged 40–74, which mainly asked about lifestyle factors, such as socio-demographic situation, personal medical history, smoking, alcohol and dietary habits. We obtained informed consent from each participant to participate in this long follow-up study of at least 20 years, including consent to the potential use of their residence registry, medical records, medical fee receipts, care insurance etc., and to the provision of biospecimens (blood and urine), including genomic analysis. Results: As of December 31, 2016, we have established a population-based cohort of 115,385 persons (Response rate 44.1%), among whom 55,278 (47.9% of participants) have provided blood and urine samples. The participation rate was slightly higher among females and in the older age group. Conclusion: We have established a large-scale population-based cohort for next-generation epidemiological study in Japan.

Background/objectivesThe association of fermented soy products, separately from total soy products, with cardiovascular disease (CVD) and total cancer has not been reported. We examined this association in a population-based prospective cohort study in Japan.Subjects/methodsWe studied 79,648 participants (42,788 women; 36,860 men) aged 45–74 years without a history of cancer, myocardial infarction, or stroke. Participants completed a food frequency questionnaire (1995–1998) and were followed to 2009–2012. Cox proportional hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of incidence of CVD and total cancer according to quartiles of total soy products, nonfermented soy products, fermented soy products, miso soup, natto, total isoflavones from soy products, isoflavones from nonfermented soy products, and isoflavones from fermented soy products.ResultsIn women, we observed a significant inverse association between fermented soy product intake and the risk of CVD (multivariate HR in the highest compared with the lowest quartile of fermented soy product intake: 0.80; 95% CI: 0.68, 0.95; P for trend = 0.010), and also found significant inverse associations for natto and isoflavones among fermented soy products. In site-specific analysis, we observed a similar, significant inverse association between fermented soy product intake and the risk of stroke in women. We found no significant association between any soy product and risk of CVD in men or total cancer in both sexes.ConclusionsIntake of fermented soy products such as natto was inversely associated with the risk of CVD in women.