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Background Trimethylamine N -oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities. Objectives To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia. Methods Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant. Results After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = −0.126 for a 5% energy increase from plant protein and −0.123 for a 1 serving/d increase of nuts). Although the animal protein–TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = −0.047) and blood pressure (β = −0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses. Conclusions In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation. [ABSTRACT FROM AUTHOR]

The root of Asian ginseng ( Panax ginseng C.A. Meyer) has been used for centuries in Oriental medicine to improve general well-being and to relieve various medical conditions. It is commonly understood that ginsenosides are responsible for the pharmacological activities of ginseng. Compared to the root of ginseng, studies on the berry are considerably limited. In this study, we evaluated the effects of polysaccharides from Asian ginseng berries on plasma lipid levels, chemically-induced enteric inflammation and neoplasm, and cancer chemoprevention in different experimental models. We tested two polysaccharide preparations: regular ginseng berry polysaccharide extract (GBPE) and ginseng berry polysaccharide portion (GBPP, removed MV ). We first observed that both oral GBPE and oral GBPP significantly reduced plasma cholesterol and triglycerides levels in a dose-related manner in ob/ob mice, without obvious body weight changes. Then, in AOM/DSS-induced acute colitis mice, GBPE and GBPP significantly ameliorated the increased gut disease activity index and inhibited the reduction of the colon length. Further, the berry polysaccharides significantly suppressed chemically-induced pro-inflammatory cytokine levels. This is consistent with the observation that GBPE and GBPP attenuated tumorigenesis in mice by significantly and dose-dependently reducing tumor load. Finally, in vitro HCT-116 and HT-29 human colon cancer cells were used. While these berry preparations had better antiproliferation effects on the HCT-116 than the HT-29 cells, the GBPE had significantly stronger inhibitory effects than GBPP. The observed in vitro GBPE's effect could contribute to the actions of its small-molecule non-polysaccharide compounds due to their direct antiproliferative activities. Results obtained from the present study suggest that ginseng berry polysaccharides may have a therapeutic role in the management of high lipid levels, enteric inflammation, and colon malignancies. [ABSTRACT FROM AUTHOR]

: Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia. Please see later in the article for the Editors' Summary [ABSTRACT FROM AUTHOR]

To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10?6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10?18), 6q22.2 (rs9387478, P = 4.14 × 10?10) and 6p21.32 (rs2395185, P = 9.51 × 10?9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. [ABSTRACT FROM AUTHOR]

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma ( p = 7.3 × 10); however, this association did not achieve genome-wide significance ( p ≤ 10) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [ n = 2,529 cases; p = 7.1 × 10; allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung ( n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking. [ABSTRACT FROM AUTHOR]

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10?8), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10?7. Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations. [ABSTRACT FROM AUTHOR]

Obesity is a disorder with a complex genetic etiology, and its epidemic is a worldwide problem. Although multiple genetic loci associated with body mass index, the most common measure of obesity, have been identified in European populations, few studies have focused on Asian populations. Here we report a genome-wide association study and replication studies with 62,245 east Asian subjects, which identified two new body mass index-associated loci in the CDKAL1 locus at 6p22 (rs2206734, P = 1.4 × 10?11) and the KLF9 locus at 9q21 (rs11142387, P = 1.3 × 10?9), as well as several previously reported loci (the SEC16B, BDNF, FTO, MC4R and GIPR loci, P < 5.0 × 10?8). We subsequently performed gene-gene interaction analyses and identified an interaction (P = 2.0 × 10?8) between a SNP in the KLF9 locus (rs11142387) and one in the MSTN (also known as GDF8) locus at 2q32 (rs13034723). These findings should provide useful insights into the etiology of obesity. [ABSTRACT FROM AUTHOR]

Background: Most studies that have evaluated the association between the body-mass index (BMI) and the risks of death from any cause and from specific causes have been conducted in populations of European origin. Methods: We performed pooled analyses to evaluate the association between BMI and the risk of death among more than 1.1 million persons recruited in 19 cohorts in Asia. The analyses included approximately 120,700 deaths that occurred during a mean follow-up period of 9.2 years. Cox regression models were used to adjust for confounding factors. Results: In the cohorts of East Asians, including Chinese, Japanese, and Koreans, the lowest risk of death was seen among persons with a BMI (the weight in kilograms divided by the square of the height in meters) in the range of 22.6 to 27.5. The risk was elevated among persons with BMI levels either higher or lower than that range — by a factor of up to 1.5 among those with a BMI of more than 35.0 and by a factor of 2.8 among those with a BMI of 15.0 or less. A similar U-shaped association was seen between BMI and the risks of death from cancer, from cardiovascular diseases, and from other causes. In the cohorts comprising Indians and Bangladeshis, the risks of death from any cause and from causes other than cancer or cardiovascular disease were increased among persons with a BMI of 20.0 or less, as compared with those with a BMI of 22.6 to 25.0, whereas there was no excess risk of either death from any cause or cause-specific death associated with a high BMI. Conclusions: Underweight was associated with a substantially increased risk of death in all Asian populations. The excess risk of death associated with a high BMI, however, was seen among East Asians but not among Indians and Bangladeshis. N Engl J Med 2011;364:719-29. [ABSTRACT FROM AUTHOR]

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women. [ABSTRACT FROM AUTHOR]

Background: Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing disease and the first 5 years of follow-up.Methods: Of 10 625 411 participants in Asia, Australia and New Zealand, Europe, and North America from 239 prospective studies (median follow-up 13·7 years, IQR 11·4-14·7), 3 951 455 people in 189 studies were never-smokers without chronic diseases at recruitment who survived 5 years, of whom 385 879 died. The primary analyses are of these deaths, and study, age, and sex adjusted hazard ratios (HRs), relative to BMI 22·5-<25·0 kg/m(2).Findings: All-cause mortality was minimal at 20·0-25·0 kg/m(2) (HR 1·00, 95% CI 0·98-1·02 for BMI 20·0-<22·5 kg/m(2); 1·00, 0·99-1·01 for BMI 22·5-<25·0 kg/m(2)), and increased significantly both just below this range (1·13, 1·09-1·17 for BMI 18·5-<20·0 kg/m(2); 1·51, 1·43-1·59 for BMI 15·0-<18·5) and throughout the overweight range (1·07, 1·07-1·08 for BMI 25·0-<27·5 kg/m(2); 1·20, 1·18-1·22 for BMI 27·5-<30·0 kg/m(2)). The HR for obesity grade 1 (BMI 30·0-<35·0 kg/m(2)) was 1·45, 95% CI 1·41-1·48; the HR for obesity grade 2 (35·0-<40·0 kg/m(2)) was 1·94, 1·87-2·01; and the HR for obesity grade 3 (40·0-<60·0 kg/m(2)) was 2·76, 2·60-2·92. For BMI over 25·0 kg/m(2), mortality increased approximately log-linearly with BMI; the HR per 5 kg/m(2) units higher BMI was 1·39 (1·34-1·43) in Europe, 1·29 (1·26-1·32) in North America, 1·39 (1·34-1·44) in east Asia, and 1·31 (1·27-1·35) in Australia and New Zealand. This HR per 5 kg/m(2) units higher BMI (for BMI over 25 kg/m(2)) was greater in younger than older people (1·52, 95% CI 1·47-1·56, for BMI measured at 35-49 years vs 1·21, 1·17-1·25, for BMI measured at 70-89 years; pheterogeneity<0·0001), greater in men than women (1·51, 1·46-1·56, vs 1·30, 1·26-1·33; pheterogeneity<0·0001), but similar in studies with self-reported and measured BMI.Interpretation: The associations of both overweight and obesity with higher all-cause mortality were broadly consistent in four continents. This finding supports strategies to combat the entire spectrum of excess adiposity in many populations.Funding: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, US National Institutes of Health. [ABSTRACT FROM AUTHOR]

• The interaction between coal use and cumulative genetic susceptibility to lung cancer is unclear. • We found weaker genetic susceptibility to lung adenocarcinoma among coal users who never smoked. • Lung cancer pathogenesis may differ depending on exposure to coal combustion products. We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature. [ABSTRACT FROM AUTHOR]

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust., (© 2024 UICC.)

Importance: The global burden of obesity is increasing, as are colorectal cancer (CRC) incidence and mortality., Objectives: To assess the association between body mass index (BMI) and risks of incident CRC and CRC-related death in the Asian population., Design, Setting, and Participants: This cohort study includes data pooled from 17 prospective cohort studies included in The Asia Cohort Consortium. Cohort enrollment was conducted from January 1, 1984, to December 31, 2002. Median follow-up time was 15.2 years (IQR, 12.1-19.2 years). Data were analyzed from January 15, 2023, through January 15, 2024., Exposure: Body mass index, calculated as weight in kilograms divided by height in meters squared., Main Outcomes and Measures: The primary outcomes were CRC incidence and CRC-related mortality. The risk of events is reported as adjusted hazard ratios (AHRs) and 95% CIs for incident CRC and death from CRC using the Cox proportional hazards regression model., Results: To assess the risk of incident CRC, 619 981 participants (mean [SD] age, 53.8 [10.1] years; 52.0% female; 11 900 diagnosed incident CRC cases) were included in the study, and to assess CRC-related mortality, 650 195 participants (mean [SD] age, 53.5 [10.2] years; 51.9% female; 4550 identified CRC deaths) were included in the study. A positive association between BMI and risk of CRC was observed among participants with a BMI greater than 25.0 to 27.5 (AHR, 1.09 [95% CI, 1.03-1.16]), greater than 27.5 to 30.0 (AHR, 1.19 [95% CI, 1.11-1.29]), and greater than 30.0 (AHR, 1.32 [95% CI, 1.19-1.46]) compared with those with a BMI greater than 23.0 to 25.0 (P < .001 for trend), and BMI was associated with a greater increase in risk for colon cancer than for rectal cancer. A similar association between BMI and CRC-related death risk was observed among participants with a BMI greater than 27.5 (BMI >27.5-30.0: AHR, 1.18 [95% CI, 1.04-1.34]; BMI >30.0: AHR, 1.38 [95% CI, 1.18-1.62]; P < .001 for trend) and was present among men with a BMI greater than 30.0 (AHR, 1.87 [95% CI, 1.49-2.34]; P < .001 for trend) but not among women (P = .15 for trend) (P = .02 for heterogeneity)., Conclusions and Relevance: In this cohort study that included a pooled analysis of 17 cohort studies comprising participants across Asia, a positive association between BMI and CRC incidence and related mortality was found. The risk was greater among men and participants with colon cancer. These findings may have implications to better understand the burden of obesity on CRC incidence and related deaths in the Asian population.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case-control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study., Methods: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes., Results: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32-1.58), similarly in males (1.44, 1.31-1.59) and females (1.45, 1.23-1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00-1.60) and non-cardia subsites (1.49, 1.35-1.65), and with intestinal- (1.48, 1.30-1.70) and diffuse-type (1.59, 1.35-1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19-1.41)., Conclusions: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer., (© 2024. The Author(s).)

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time., (© 2024 UICC.)

Background: Evidence suggests a possible link between diabetes and gastric cancer risk, but the findings remain inconclusive, with limited studies in the Asian population. We aimed to assess the impact of diabetes and diabetes duration on the development of gastric cancer overall, by anatomical and histological subtypes., Methods: A pooled analysis was conducted using 12 prospective studies included in the Asia Cohort Consortium. Among 558 981 participants (median age 52), after a median follow-up of 14.9 years and 10.5 years, 8556 incident primary gastric cancers and 8058 gastric cancer deaths occurred, respectively. Cox proportional hazard regression models were used to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) and pooled using random-effects meta-analyses., Results: Diabetes was associated with an increased incidence of overall gastric cancer (HR 1.15, 95% CI 1.06-1.25). The risk association did not differ significantly by sex (women vs men: HR 1.31, 95% CI 1.07-1.60 vs 1.12, 1.01-1.23), anatomical subsites (noncardia vs cardia: 1.14, 1.02-1.28 vs 1.17, 0.77-1.78) and histological subtypes (intestinal vs diffuse: 1.22, 1.02-1.46 vs 1.00, 0.62-1.61). Gastric cancer risk increased significantly during the first decade following diabetes diagnosis (HR 4.70, 95% CI 3.77-5.86), and decreased with time (nonlinear p < .01). Positive associations between diabetes and gastric cancer mortality were observed (HR 1.15, 95% CI 1.03-1.28) but attenuated after a 2-year time lag., Conclusion: Diabetes was associated with an increased gastric cancer incidence regardless of sex, anatomical subsite, or subtypes of gastric cancer. The risk of gastric cancer was particularly high during the first decade following diabetes diagnosis., (© 2024 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m 2 ); normal (18.5-22.9 kg/m 2 ); overweight (23-24.9 kg/m 2 ); and obese (25+ kg/m 2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis., (© 2023 UICC.)

Background: The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium., Methods: We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs., Results: A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI <18.5 kg/m2: HR = 2.20, 95% CI 1.80-2.70) and extreme obesity (BMI ≥35 kg/m2: HR = 4.38, 95% CI 2.25-8.52) relative to the reference BMI (23-25 kg/m2). This association pattern was confirmed by several alternative analyses based on OC incidence and meta-analysis. A similar wide J-shaped association was observed in oesophageal squamous cell carcinoma (OSCC). Smoking and alcohol synergistically increased the OC mortality risk in underweight participants (HR = 6.96, 95% CI 4.54-10.67) relative to that in reference BMI participants not exposed to smoking and alcohol., Conclusion: Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case-control study is recommended., (© The Author(s) 2022; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Colorectal cancer is a leading cancer incidence and cause of death worldwide and in Vietnam. Although screening is considered an effective measure to prevent and control colorectal cancer, there is no such effort in Vietnam., Methods: Between 01 January 2018 and 31 October 2019, a population-based colorectal cancer screening program was conducted in Hanoi, Vietnam. A health advocacy campaign and follow-up phone calls were used to enroll residents aged ≥40 years old to complete an immunochemical-fecal occult blood testing. Positive immunochemical-fecal occult blood testing was followed by a colonoscopy. We also conducted a systematic review of the colorectal cancer screening programs in the Asia-Pacific region that used similar approach by searching Ovid Medline and PubMed databases., Results: During study period, 103 542 individuals among 672 742 eligible residents attended the screening of whom 81.5% participants finished immunochemical-fecal occult blood testing test and the positive rate was 6.1%. The coverage rate for immunochemical-fecal occult blood testing test was 11.9%. Among 2278 individuals who underwent colonoscopy, 3.5% were histologically diagnosed with cancer, 17.8% with advanced adenomas, and 23.1% with non-advanced adenomas. Males had significantly higher detection rate of advanced adenomas, cancer or ≥ two polyps/tumor than females (P < 0.0001). The systematic review showed that in two-step modality (i.e. immunochemical-fecal occult blood testing/fecal immunochemical test and colonoscopy), the test positive was from 4.1 to 10.6%. Once colonoscopy was performed subsequently, the rate of cancer among positive participants was from 1.7 to 16.4% and that of advanced adenomas was from 7.1 to 23.1%., Conclusion: We showed that the two-step modality is a promising strategy for colorectal cancer screening in Vietnam that might apply to similar settings with limited resources., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations., Methods: We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model., Results: In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption., Conclusions: In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Importance: Marital status has been shown to be associated with mortality, but evidence in Asian populations is limited., Objective: To examine the association of marital status with total and cause-specific mortality., Design, Setting, and Participants: This cohort study included individual participant data from 16 prospective studies in the Asia Cohort Consortium conducted between 1963 and 2015. Asian participants with complete information on marital and vital status were included. Study-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards model and then pooled using a random-effects meta-analysis. The analysis began in February 2021 and ended in August 2021., Exposures: Marital status., Main Outcomes and Measures: All-cause and cause-specific mortality., Results: Of 623 140 participants (326 397 women [52.4%] and 296 743 men [47.6%]; mean [SD] age, 53.7 [10.2] years; mean [SD] follow-up time, 15.5 [6.1] years), 123 264 deaths were ascertained. Compared with married individuals, those who were unmarried had pooled HRs of 1.15 (95% CI, 1.07-1.24) for total mortality, 1.12 (95% CI, 1.03-1.22) for cerebrovascular disease mortality, 1.20 (95% CI, 1.09-1.31) for coronary heart disease mortality, 1.17 (95% CI, 1.07-1.28) for circulatory system diseases mortality, 1.06 (95% CI, 1.01-1.11) for cancer mortality, 1.14 (95% CI, 1.05-1.23) for respiratory diseases mortality, and 1.19 (95% CI, 1.05-1.34) for external causes of death. Positive associations with total mortality were also observed for those who were single (HR, 1.62; 95% CI, 1.41-1.86), separated (HR, 1.35; 95% CI, 1.13-1.61), divorced (HR, 1.38; 95% CI, 1.13-1.69), and widowed (HR, 1.09; 95% CI, 1.04-1.13). In subgroup analyses, the positive association persisted across baseline health conditions, and the risk of death was more pronounced among men or people younger than 65 years., Conclusions and Relevance: This large pooled cohort study of individual participant data provides strong evidence that being unmarried, as well as belonging to the unmarried subcategories, was positively associated with total and cause-specific mortality. Investment of targeted social support services might need to be considered in light of the mortality differences between married and unmarried individuals.

Background: Although previous meta-analyses have suggested a dose-response relationship between body mass index (BMI) and thyroid cancer risk, limited evidence has been presented about Asian populations. To assess this association among Asian populations, where underweight is more prevalent than in other regions, a pooled analysis from the Asia Cohort Consortium was conducted. Methods: Baseline height and weight were measured in five cohorts and self-reported in eight cohorts. Thyroid cancer incidence was ascertained by linkage to local cancer registries. Cohorts were treated as a stratum in the Cox proportional hazard model to estimate the pooled hazard ratios (HRs) and corresponding confidence intervals (CIs) from the estimates for each cohort. All analyses were stratified by sex. Results: A total of 538,857 men and women from 13 cohorts from mainland China, Korea, Japan, and Singapore were included in the analysis. During a mean of 15.1 years of follow-up, 1132 thyroid cancer cases were ascertained. Using a BMI of 18.5-22.9 kg/m 2 as a reference, an elevated risk of thyroid cancer was observed for groups with a BMI between 25 and 29.9 kg/m 2 (HR: 1.31, [CI: 0.95-1.80]) and a BMI of 30 kg/m 2 and greater (HR: 1.84, [CI: 0.89-3.81]) in men. Thyroid cancer risk was elevated in women with a BMI of 23-24.9 kg/m 2 (HR: 1.26, [CI: 1.07-1.48]). The HRs for 5-U increment of BMI showed a linear association among men (HR: 1.25, [CI 1.10-1.55]) but not among women (HR: 1.07, [CI: 0.97-1.18]). Although the overall thyroid cancer risk was lower among underweight men and women, the papillary cancer risk may be elevated among underweight men (HR: 2.24, [CI: 0.75-6.66]). Conclusion: While higher BMI is associated with an elevated risk of thyroid cancer in both men and women, the association of underweight BMI may differ by sex and histological subtype.

Background: Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia., Methods: Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis., Results: During a mean follow-up of 12.0 years, 108 287 deaths were ascertained-35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10-14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13-1.37) and 1.20 (1.02-1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15-19 years after smoking cessation [1.97 (1.41-2.73)], particularly among former heavy smokers [2.62 (1.71-4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries., Conclusions: Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts., Methods: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis., Findings: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence., Conclusions: Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.

Importance: Dietary fiber (the main source of prebiotics) and yogurt (a probiotic food) confer various health benefits via modulating the gut microbiota and metabolic pathways. However, their associations with lung cancer risk have not been well investigated., Objective: To evaluate the individual and joint associations of dietary fiber and yogurt consumption with lung cancer risk and to assess the potential effect modification of the associations by lifestyle and other dietary factors., Design, Setting, and Participants: This pooled analysis included 10 prospective cohorts involving 1 445 850 adults from studies that were conducted in the United States, Europe, and Asia. Data analyses were performed between November 2017 and February 2019. Using harmonized individual participant data, hazard ratios and 95% confidence intervals for lung cancer risk associated with dietary fiber and yogurt intakes were estimated for each cohort by Cox regression and pooled using random-effects meta-analysis. Participants who had a history of cancer at enrollment or developed any cancer, died, or were lost to follow-up within 2 years after enrollment were excluded., Exposures: Dietary fiber intake and yogurt consumption measured by validated instruments., Main Outcomes and Measures: Incident lung cancer, subclassified by histologic type (eg, adenocarcinoma, squamous cell carcinoma, and small cell carcinoma)., Results: The analytic sample included 627 988 men, with a mean (SD) age of 57.9 (9.0) years, and 817 862 women, with a mean (SD) age of 54.8 (9.7) years. During a median follow-up of 8.6 years, 18 822 incident lung cancer cases were documented. Both fiber and yogurt intakes were inversely associated with lung cancer risk after adjustment for status and pack-years of smoking and other lung cancer risk factors: hazard ratio, 0.83 (95% CI, 0.76-0.91) for the highest vs lowest quintile of fiber intake; and hazard ratio, 0.81 (95% CI, 0.76-0.87) for high vs no yogurt consumption. The fiber or yogurt associations with lung cancer were significant in never smokers and were consistently observed across sex, race/ethnicity, and tumor histologic type. When considered jointly, high yogurt consumption with the highest quintile of fiber intake showed more than 30% reduced risk of lung cancer than nonyogurt consumption with the lowest quintile of fiber intake (hazard ratio, 0.67 [95% CI, 0.61-0.73] in total study populations; hazard ratio, 0.69 [95% CI, 0.54-0.89] in never smokers), suggesting potential synergism., Conclusions and Relevance: Dietary fiber and yogurt consumption was associated with reduced risk of lung cancer after adjusting for known risk factors and among never smokers. Our findings suggest a potential protective role of prebiotics and probiotics against lung carcinogenesis.

Background: To date, few epidemiologic studies have been conducted to elucidate lifestyle-related risk factors for multiple myeloma in Asia. We investigated the association of body mass index (BMI), smoking, and alcohol intake with the risk of multiple myeloma mortality through a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium., Methods: The analysis included 805,309 participants contributing 10,221,623 person-years of accumulated follow-up across Asia Cohort Consortium cohorts. HRs and 95% confidence intervals (95% CI) for the association between BMI, smoking, and alcohol at baseline and the risk of multiple myeloma mortality were assessed using a Cox proportional hazards model with shared frailty., Results: We observed a statistically significant dose-dependent association between BMI categories and the risk of multiple myeloma mortality (<18.5 kg/m 2 : HR = 0.80, 95% CI: 0.52-1.24; 18.5-24.9 kg/m 2 : reference; 25.0-29.9 kg/m 2 : HR = 1.17, 95% CI: 0.94-1.47; ≥30 kg/m 2 : HR = 1.61, 95% CI: 0.99-2.64, P trend = 0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes = 0.150). We observed no significant associations between smoking or alcohol consumption and risk of multiple myeloma mortality., Conclusions: This study showed that excess body mass is associated with an increased risk of multiple myeloma mortality among Asian populations. In contrast, our results do not support an association between smoking or alcohol consumption and the risk of multiple myeloma mortality in Asian populations., Impact: This study provides important evidence on the association of BMI, smoking, and alcohol with the risk of multiple myeloma mortality in Asian populations., (©2019 American Association for Cancer Research.)

Objective: To study the association of educational level and risk of death from all causes, cardiovascular disease (CVD) and cancer among Asian populations., Design: A pooled analysis of 15 population-based cohort studies., Setting and Participants: 694 434 Asian individuals from 15 prospective cohorts within the Asia Cohort Consortium., Interventions: None., Main Outcome Measures: HRs and 95% CIs for all-cause mortality, as well as for CVD-specific mortality and cancer-specific mortality., Results: A total of 694 434 participants (mean age at baseline=53.2 years) were included in the analysis. During a mean follow-up period of 12.5 years, 103 023 deaths were observed, among which 33 939 were due to cancer and 34 645 were due to CVD. Higher educational levels were significantly associated with lower risk of death from all causes compared with a low educational level (≤primary education); HRs and 95% CIs for secondary education, trade/technical education and ≥university education were 0.88 (0.85 to 0.92), 0.81 (0.73 to 0.90) and 0.71 (0.63 to 0.80), respectively (p trend =0.002). Similarly, HRs (95% CIs) were 0.93 (0.89 to 0.97), 0.86 (0.78 to 0.94) and 0.81 (0.73 to 0.89) for cancer death, and 0.88 (0.83 to 0.93), 0.77 (0.66 to 0.91) and 0.67 (0.58 to 0.77) for CVD death with increasing levels of education (both p trend <0.01). The pattern of the association among East Asians and South Asians was similar compared with ≤primary education; HR (95% CI) for all-cause mortality associated with ≥university education was 0.72 (0.63 to 0.81) among 539 724 East Asians (Chinese, Japanese and Korean) and 0.61 (0.54 to 0.69) among 154 710 South Asians (Indians and Bangladeshis)., Conclusion: Higher educational level was associated with substantially lower risk of death among Asian populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations., Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status., Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018., Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status., Main Outcomes and Measures: All-cause and cause-specific mortality., Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction < .001) and more evident among adults aged 30 to 49 years (HR, 2.43; 95% CI, 2.08-2.84) than among adults aged 70 years and older (HR, 1.51; 95% CI, 1.40-1.62) (P for interaction < .001). A similar pattern of association was found between diabetes and cause-specific mortality, with significant variations noted by sex and age., Conclusions and Relevance: This study found that diabetes was associated with increased risk of death from several diseases among Asian populations. Development and implementation of diabetes management programs are urgently needed to reduce the burden of diabetes in Asia.

Background & Aims: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations., Methods: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels., Results: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10 -8 . We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci., Conclusions: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Importance: Understanding birth cohort-specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations., Objectives: To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations., Design, Setting, and Participants: This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India., Exposures: Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking., Main Outcomes and Measures: Country or region and birth cohort-specific mortality and the population attributable risk for deaths from all causes and from lung cancer., Results: Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions., Conclusions and Relevance: In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Background: Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry., Methods: We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk., Results: We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively., Conclusion: Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.

Objective: This study examined the proportion of overweight in schizophrenia inpatients in selected Asian countries and territories and its independent demographic and clinical correlates., Method: Data on 1,534 hospitalized schizophrenia patients in 9 Asian countries and territories were collected by a review of medical files supplemented by a clinical interview during a 1-month period. Patients' sociodemographic and clinical characteristics, prescriptions of psychotropic drugs, and Body Mass Index (BMI) were recorded using a standardized protocol and data collection procedure. For analyzes, BMI ≥ 25 kg/m2 was defined as overweight., Results: The proportion of overweight was 35.8% (549/1,534) in the entire sample, with 39.7% (224/564) in females and 33.5% (325/970) in males (p = 0.01) and with wide inter-country variations. Multiple logistic regression analysis revealed that after controlling for study sites, overweight was independently associated with more frequent use of mood stabilizers (p < 0.001, odds ration (OR) = 1.4, 95% confidence interval (CI) = 1.1-1.8) and longer length of illness (p < 0.001, OR = 1.6, 95% CI = 1.2-2.1) but was less likely found in male patients (p = 0.003, OR = 0.7, 95% CI = 0.5-0.8)., Conclusions: The prevalence of overweight Asian schizophrenia patients is significantly lower than the reported figures among their Western counterparts. There is considerable variation in prevalence of overweight schizophrenia patients within Asian countries and territories.

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.

Many potentially modifiable risk factors for prostate cancer are also associated with prostate cancer screening, which may induce a bias in epidemiologic studies. We investigated the associations of body mass index (weight (kg)/height (m)(2)), smoking, and alcohol consumption with risk of fatal prostate cancer in Asian countries where prostate cancer screening is not widely utilized. Analysis included 18 prospective cohort studies conducted during 1963-2006 across 6 countries in southern and eastern Asia that are part of the Asia Cohort Consortium. Body mass index, smoking, and alcohol intake were determined by questionnaire at baseline, and cause of death was ascertained through death certificates. Analysis included 522,736 men aged 54 years, on average, at baseline. During 4.8 million person-years of follow-up, there were 634 prostate cancer deaths (367 prostate cancer deaths across the 11 cohorts with alcohol data). In Cox proportional hazards analyses of all cohorts in the Asia Cohort Consortium, prostate cancer mortality was not significantly associated with obesity (body mass index >25: hazard ratio (HR) = 1.08, 95% confidence interval (CI): 0.85, 1.36), ever smoking (HR = 1.00, 95% CI: 0.84, 1.21), or heavy alcohol intake (HR = 1.00, 95% CI: 0.74, 1.35). Differences in prostate cancer screening and detection probably contribute to differences in the association of obesity, smoking, or alcohol intake with prostate cancer risk and mortality between Asian and Western populations and thus require further investigation., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians., Design: Pooled analyses of 20 prospective cohorts in Asia, including data from 835,082 east Asians and 289,815 south Asians. Cohorts were identified through a systematic search of the literature in early 2008, followed by a survey that was sent to each cohort to assess data availability., Setting: General populations in east Asia (China, Taiwan, Singapore, Japan, and Korea) and south Asia (India and Bangladesh)., Participants: 1,124,897 men and women (mean age 53.4 years at baseline)., Main Outcome Measures: Risk of death from overall cardiovascular disease, coronary heart disease, stroke, and (in east Asians only) stroke subtypes., Results: 49,184 cardiovascular deaths (40,791 in east Asians and 8393 in south Asians) were identified during a mean follow-up of 9.7 years. East Asians with a body mass index of 25 or above had a raised risk of death from overall cardiovascular disease, compared with the reference range of body mass index (values 22.5-24.9; hazard ratio 1.09 (95% confidence interval 1.03 to 1.15), 1.27 (1.20 to 1.35), 1.59 (1.43 to 1.76), 1.74 (1.47 to 2.06), and 1.97 (1.44 to 2.71) for body mass index ranges 25.0-27.4, 27.5-29.9, 30.0-32.4, 32.5-34.9, and 35.0-50.0, respectively). This association was similar for risk of death from coronary heart disease and ischaemic stroke; for haemorrhagic stroke, the risk of death was higher at body mass index values of 27.5 and above. Elevated risk of death from cardiovascular disease was also observed at lower categories of body mass index (hazard ratio 1.19 (95% confidence interval 1.02 to 1.39) and 2.16 (1.37 to 3.40) for body mass index ranges 15.0-17.4 and <15.0, respectively), compared with the reference range. In south Asians, the association between body mass index and mortality from cardiovascular disease was less pronounced than that in east Asians. South Asians had an increased risk of death observed for coronary heart disease only in individuals with a body mass index greater than 35 (hazard ratio 1.90, 95% confidence interval 1.15 to 3.12)., Conclusions: Body mass index shows a U shaped association with death from overall cardiovascular disease among east Asians: increased risk of death from cardiovascular disease is observed at lower and higher ranges of body mass index. A high body mass index is a risk factor for mortality from overall cardiovascular disease and for specific diseases, including coronary heart disease, ischaemic stroke, and haemorrhagic stroke in east Asians. Higher body mass index is a weak risk factor for mortality from cardiovascular disease in south Asians.

We aimed to examine the association between BMI and the risk of death from pancreas cancer in a pooled analysis of data from the Asia Cohort Consortium. The data for this pooled analysis included 883 529 men and women from 16 cohort studies in Asian countries. Cox proportional-hazards models were used to estimate the hazard ratios and 95% confidence intervals for pancreas cancer mortality in relation to BMI. Seven predefined BMI categories (<18.5, 18.5-19.9, 20.0-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.9, ≥ 30) were used in the analysis, with BMI of 22.5-24.9 serving as the reference group. The multivariable analyses were adjusted for known risk factors, including age, smoking, and a history of diabetes. We found no statistically significant overall association between each BMI category and the risk of death from pancreas cancer in all Asians, and obesity was unrelated to the risk of mortality in both East Asians and South Asians. Age, smoking, and a history of diabetes did not modify the association between BMI and the risk of death from pancreas cancer. In planned subgroup analyses among East Asians, an increased risk of death from pancreas cancer among those with a BMI less than 18.5 was observed for individuals with a history of diabetes; hazard ratio=2.01 (95% confidence interval: 1.01-4.00) (P for interaction=0.07). The data do not support an association between BMI and the risk of death from pancreas cancer in these Asian populations.

Although approximately 20 common genetic susceptibility loci have been identified for breast cancer risk through genome-wide association studies (GWASs), genetic risk variants reported to date explain only a small fraction of heritability for this common cancer. We conducted a four-stage GWAS including 17 153 cases and 16 943 controls among East-Asian women to search for new genetic risk factors for breast cancer. After analyzing 684 457 SNPs in 2062 cases and 2066 controls (Stage I), we selected for replication among 5969 Chinese women (4146 cases and 1823 controls) the top 49 SNPs that had neither been reported previously nor were in strong linkage disequilibrium with reported SNPs (Stage II). Three SNPs were further evaluated in up to 13 152 Chinese and Japanese women (6436 cases and 6716 controls) (Stage III). Finally, two SNPs were evaluated in 10 847 Korean women (4509 cases and 6338 controls) (Stage IV). SNP rs10822013 on chromosome 10q21.2, located in the zinc finger protein 365 (ZNF365) gene, showed a consistent association with breast cancer risk in all four stages with a combined per-risk allele odds ratio of 1.10 (95% CI: 1.07-1.14) (P-value for trend = 5.87 × 10(-9)). In vitro electrophoretic mobility shift assays demonstrated the potential functional significance of rs10822013. Our results strongly implicate rs10822013 at 10q21.2 as a genetic risk variant for breast cancer among East-Asian women.