Search

Abstract Adiposity is an established risk factor for multiple diseases, but the causal relationships of different adiposity types with circulating protein biomarkers have not been systematically investigated. We examine the causal associations of general and central adiposity with 2923 plasma proteins among 3977 Chinese adults (mean BMI = 23.9 kg/m²). Genetically-predicted body mass index (BMI), body fat percentage (BF%), waist circumference (WC), and waist-to-hip ratio (WHR) are significantly (FDR

Abstract Background Despite major primary health care (PHC) reforms in China with the 2009 launch of the National Essential Public Health Service Package, the country experiences many challenges in improving the management of non-communicable diseases in PHC facilities. “EMERALD” is a multifaceted implementation strategy to strengthen the management of hypertension and type-2 diabetes mellitus (T2DM) in PHC facilities. The study aims to: (1) examine the effectiveness of EMERALD in improving hypertension and T2DM management; (2) evaluate the implementation of the interventions; and (3) use the study findings to model the long-term health economic impact of the interventions. Methods The EMERALD intervention components include: (1) empowerment for PHC providers through training and capacity building; (2) empowerment for patient communities through multi-media health education; and (3) empowerment for local health administrators through health data monitoring and strengthening governance of local PHC programs. An interrupted time series design will be used to determine the effectiveness of the interventions based on routinely collected health data extracted from local health information systems. The primary effectiveness outcome is the guideline-recommended treatment rates for people with hypertension and T2DM. Secondary effectiveness outcomes include hypertension and T2DM diagnosis and control rates, and enrolment and adherence rates to the recommended care processes in the National Essential Public Health Service Package. A mixed-methods process evaluation will be conducted to evaluate the implementation of the interventions, including the reach of the target population, adequacy of adoption, level of implementation fidelity, and maintenance. Qualitative interviews with policy makers, health administrators, PHC providers, and patients with hypertension and/or T2DM will be conducted to further identify factors influencing the implementation. In addition, health economic modelling will be performed to explore the long-term incremental costs and benefits of the interventions. Discussion This study is expected to generate important evidence on the effectiveness, implementation, and health economic impact of complex PHC interventions to strengthen the primary care sector’s contribution to addressing the growing burden of non-communicable diseases in China. Trial registration The study has been registered on Chinese Clinical Trial Registry at https://www.chictr.org.cn/ (Registration number ChiCTR2400082036, on March 19th 2024).

Abstract Background There is no consensus on the cause and effect of systemic chronic inflammation (SCI) regarding chronic obstructive pulmonary disease (COPD). The impact of second-hand smoke (SHS) on COPD has reached inconsistent conclusions. Methods The China Kadoorie Biobank cohort was followed up from the 2004–08 baseline survey to 31 December 2018. Among the selected 445,523 participants in the final analysis, Cox and linear regressions were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of tobacco exposure with COPD risk and baseline levels of log-transformed inflammatory factors [βs (95% CIs)], respectively. Results Participants were followed up for a median of 12.1 years and 11,825 incident COPD events were documented. Ever-smokers were associated with a higher risk of COPD than non-smokers with non-weekly SHS exposure. A younger age to start smoking, a greater amount of daily tobacco consumption, and deeper inhalation were associated with increased risk of COPD and correlated with elevated levels of plasma high-sensitivity C-reactive protein (hs-CRP, all P trend

Abstract Little is known about the prospective association between autosomal mosaic chromosomal alterations (mCAs), a group of large-scale somatic mutations on autosomes, and bladder cancer. Here we utilized data from 99,877 participants who were free of physician-diagnosed cancer at baseline (2004–2008) of the China Kadoorie Biobank to estimate the associations between autosomal mCAs and bladder cancer (ICD-10: C67). A total of 2874 autosomal mCAs events among 2612 carriers (2.6%) were detected. After a median follow-up of 12.4 years, we discovered that participants with all autosomal mCAs exhibited higher risks of bladder cancer, with a multivariable-adjusted hazard ratio (HR) (95% confidence interval [CI]) of 2.60 (1.44, 4.70). The estimate of such association was even stronger for mosaic loss events (HR [95% CI]: 6.68 [2.92, 15.30]), while it was not significant for CN-LOH events. Both expanded (cell fraction ≥10%) and non-expanded autosomal mCAs, as well as mosaic loss, were associated with increased risks of bladder cancer. Of interest, physical activity (PA) significantly modified the associations of autosomal mCAs and mosaic loss (P interaction = 0.038 and 0.012, respectively) with bladder cancer. The increased risks of bladder cancer were only observed with mCAs and mosaic loss among participants with a lower level of PA (HR [95% CI]: 5.11 [2.36, 11.09] and 16.30 [6.06, 43.81]), but not among participants with a higher level of PA. Our findings suggest that peripheral leukocyte autosomal mCAs may represent a novel risk factor for bladder cancer, and PA may serve as a potential intervention target for mCAs carriers.

Abstract DNA methylation (DNAm) has been implicated in acute coronary syndrome (ACS), but the causality remains unclear in cross-sectional studies. Here, we conduct a prospective epigenome-wide association study of incident ACS in two Chinese cohorts (discovery: 751 nested case-control pairs; replication: 476 nested case-control pairs). We identified and validated 26 differentially methylated positions (DMPs, false discovery rate [FDR]

Abstract Background The associations of vegetarian diets with risks for site-specific cancers have not been estimated reliably due to the low number of vegetarians in previous studies. Therefore, the Cancer Risk in Vegetarians Consortium was established. The aim is to describe and compare the baseline characteristics between non-vegetarian and vegetarian diet groups and between the collaborating studies. Methods We harmonised individual-level data from 11 prospective cohort studies from Western Europe, North America, South Asia and East Asia. Comparisons of food intakes, sociodemographic and lifestyle factors were made between diet groups and between cohorts using descriptive statistics. Results 2.3 million participants were included; 66% women and 34% men, with mean ages at recruitment of 57 (SD: 7.8) and 57 (8.6) years, respectively. There were 2.1 million meat eaters, 60,903 poultry eaters, 44,780 pescatarians, 81,165 vegetarians, and 14,167 vegans. Food intake differences between the diet groups varied across the cohorts; for example, fruit and vegetable intakes were generally higher in vegetarians than in meat eaters in all the cohorts except in China. BMI was generally lower in vegetarians, particularly vegans, except for the cohorts in India and China. In general, but with some exceptions, vegetarians were also more likely to be highly educated and physically active and less likely to smoke. In the available resurveys, stability of diet groups was high in all the cohorts except in China. Conclusions Food intakes and lifestyle factors of both non-vegetarians and vegetarians varied markedly across the individual cohorts, which may be due to differences in both culture and socioeconomic status, as well as differences in questionnaire design. Therefore, care is needed in the interpretation of the impacts of vegetarian diets on cancer risk.

Abstract Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk.

Abstract The primary obstacle to curing HIV-1 is a reservoir of CD4+ cells that contain stably integrated provirus. Previous studies characterizing the proviral landscape, which have been predominantly conducted in males in the United States and Europe living with HIV-1 subtype B, have revealed that most proviruses that persist during antiretroviral therapy (ART) are defective. In contrast, less is known about proviral landscapes in females with non-B subtypes, which represents the largest group of individuals living with HIV-1. Here, we analyze genomic DNA from resting CD4+ T-cells from 16 female and seven male Ugandans with HIV-1 receiving suppressive ART (n = 23). We perform near-full-length proviral sequencing at limiting dilution to examine the proviral genetic landscape, yielding 607 HIV-1 subtype A1, D, and recombinant proviral sequences (mean 26/person). We observe that intact genomes are relatively rare and clonal expansion occurs in both intact and defective genomes. Our modification of the primers and probes of the Intact Proviral DNA Assay (IPDA), developed for subtype B, rescues intact provirus detection in Ugandan samples for which the original IPDA fails. This work will facilitate research on HIV-1 persistence and cure strategies in Africa, where the burden of HIV-1 is heaviest.

Non-optimal temperature is a leading risk factor for global disease burden. Most epidemiological studies assessed only outdoor temperature, with important uncertainties on personal exposure misclassification. The CKB-Air study measured personal, household (kitchen and living room), and outdoor temperatures in the summer (MAY-SEP 2017) and winter (NOV 2017-JAN 2018) in 477 participants in China. After data cleaning, ∼88,000 person-hours of data were recorded across each microenvironment. Using multivariable linear regression (MLR) and random forest (RF) models, we identified key predictors and constructed personal temperature exposure prediction models. We used generalised additive mixed effect models to examine the relationships of personal and outdoor temperatures with heart rate. The 24-hour mean (SD) personal and outdoor temperatures were 29.2 (3.8) °C and 27.6 (6.4) °C in summer, and 12.0 (4.0) °C and 7.5 (4.2) °C in winter, respectively. The temperatures across microenvironments were strongly correlated (Spearman’s ρ: 0.86–0.92) in summer. In winter, personal temperature was strongly related to household temperatures (ρ: 0.74–0.79) but poorly related to outdoor temperature (ρ: 0.30). RF algorithm identified household and outdoor temperatures and study date as top predictors of personal temperature exposure for both seasons, and heating-related factors were important in winter. The final MLR and RF models incorporating questionnaire and device data performed satisfactorily in predicting personal exposure in both seasons (R2summer: 0.92; R2winter: 0.68–0.70). We found consistent U-shaped associations between measured and predicted personal temperature exposures and heart rate (lowest at ∼ 14.5 °C), but a weak positive linear association with outdoor temperature. Personal and outdoor temperatures differ substantially winter, but prediction models incorporating household and outdoor temperatures and questionnaire data performed satisfactorily. Exposure misclassification from using outdoor temperature may produce inappropriate epidemiological findings.

Background: Infectious diseases remain a major global health concern, including in China, with an estimated >10 million cases of infectious disease in 2019. We describe the burden of site-specific infectious diseases among Chinese adults. Methods: From 2004 to 2008, the prospective China Kadoorie Biobank enrolled 512,726 adults aged 30-79 years from 10 diverse areas (5 rural, 5 urban) of China. During the 12 years of follow-up, 101,673 participants were hospitalized for any infectious disease. Descriptive analyses examined standardized incidence, mortality and case fatality of infections. Findings: The incidence of any infectious disease was 1856 per 100,000 person-years; respiratory tract infections (1069) were most common. The infectious disease mortality rate was 31.8 per 100,000 person-years (20.3 and 9.4 for respiratory and non-respiratory infections, respectively) and case fatality was 2.2% (2.6% and 1.6% for respiratory and non-respiratory infections, respectively). Infectious disease incidence and mortality rates were higher at older ages and in rural areas. There were no clear sex differences in infectious disease incidence rates, but mortality and case fatality rates were twice as high in men as in women. Interpretation: Infectious diseases were common in Chinese adults. The observed burden of, and disparities in, site-specific infections can inform targeted prevention efforts. Funding: Kadoorie Foundation, Wellcome Trust, MRC, BHF, CR-UK, MoST, NNSF.

Abstract Background Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. Methods The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004–2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. Results During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02–1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78–0.95) for > 12 months compared with those who breastfed for 7–12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. Conclusion Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Background: Information on the association between physical activity (PA) and the risk of chronic kidney disease (CKD) is limited. We aimed to explore the associations of total, domain-specific, and intensity-specific PA with CKD and its subtypes in China. Methods: The study included 475,376 adults from the China Kadoorie Biobank aged 30–79 years during 2004–2008 at baseline. An interviewer-administered questionnaire was used to collect the information about PA, which was quantified as metabolic equivalent of task hours per day (MET-h/day) and categorized into 4 groups based on quartiles. Cox regression was used to analyze the association between PA and CKD risk. Results: During a median follow-up of 12.1 years, 5415 incident CKD cases were documented, including 1159 incident diabetic kidney disease (DKD) cases and 362 incident hypertensive nephropathy (HTN) cases. Total PA was inversely associated with CKD risk, with an adjusted hazard ratio (HR, 95% confidence interval (95%CI)) of 0.83 (0.75–0.92) for incident CKD in the highest quartile of total PA as compared with participants in the lowest quartile. Similar results were observed for risk of DKD and HTN, and the corresponding HRs (95%CIs) were 0.75 (0.58–0.97) for DKD risk and 0.56 (0.37–0.85) for HTN risk. Increased nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA were significantly associated with a decreased risk of CKD, with HRs (95%CIs) of 0.80 (0.73–0.88), 0.85 (0.77–0.94), and 0.85 (0.76–0.95) in the highest quartile, respectively. Conclusion: PA, including nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA, was inversely associated with the risk of CKD, including DKD, HTN, and other CKD, and such associations were dose dependent.

Abstract Despite the high prevalence of snoring in Asia, little is known about the genetic etiology of snoring and its causal relationships with cardiometabolic traits. Based on 100,626 Chinese individuals, a genome-wide association study on snoring was conducted. Four novel loci were identified for snoring traits mapped on SLC25A21, the intergenic region of WDR11 and FGFR, NAA25, ALDH2, and VTI1A, respectively. The novel loci highlighted the roles of structural abnormality of the upper airway and craniofacial region and dysfunction of metabolic and transport systems in the development of snoring. In the two-sample bi-directional Mendelian randomization analysis, higher body mass index, weight, and elevated blood pressure were causal for snoring, and a reverse causal effect was observed between snoring and diastolic blood pressure. Altogether, our results revealed the possible etiology of snoring in China and indicated that managing cardiometabolic health was essential to snoring prevention, and hypertension should be considered among snorers.

Background: Autoimmune diseases account for a substantial burden of disease in high-income countries, including Europe and North America. However, their epidemiology remains under-researched in other regions. We examined the incidence and prevalence of eight autoimmune diseases in the adult Chinese population through a systematic review of epidemiological studies. Methods: We searched OvidSP MEDLINE and Google Scholar from 1995 to 2023 (inclusive) for articles on the incidence or prevalence of autoimmune thyroiditis (AT), Graves' disease (GD), type 1 diabetes mellitus (T1D), multiple sclerosis (MS), Crohn's disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We included studies from mainland China, Taiwan, Hong Kong or Macau. The study is registered with PROSPERO (CRD42021225842). Findings: We retrieved 2278 records, of which 62 studies (161 estimates) were included in the systematic review, and 42 studies (101 estimates) were included in the meta-analysis. Pooled fixed-effects estimates for incidence of CD, UC, MS, T1D and SLE were 0.22 (95% CI 0.21–0.23), 1.13 (1.10–1.17), 0.28 (0.26–0.30), 2.20 (1.70–2.84) and 4.87 (4.21–5.64) per 100,000 persons, respectively. For RA, one study estimate was included, with an incidence of 15.8 per 100,000 persons. Fixed-effects estimates for the prevalence of CD, UC, MS, SLE, RA, GD and AT were 3.73 (95% CI 3.68–3.78), 16.11 (15.93–16.29), 4.08 (3.95–4.21), 93.44 (92.27–94.63), 104 (103–106), 450 (422–481) and 2322 (2057-2620), respectively, per 100,000 persons. Across all conditions, women were almost twice as likely as men to be diagnosed with an autoimmune disease. Interpretation: There is marked variation in the frequency of autoimmune diseases among Chinese adults. We estimate that 2.7–3.0% (>31 million people) of the adult Chinese population have one or more autoimmune diseases, comparable to Western populations, with the majority of the burden from autoimmune thyroid diseases and rheumatoid arthritis.

Summary: Background: In non-high-risk individuals, risk-category-based atherosclerotic cardiovascular disease (ASCVD) screening strategies may be more cost-effective than one-size-fits-all approaches. However, current decisions are constrained by a lack of research evidence. We aimed to explore appropriate risk-category-based screening interval strategies for non-high-risk individuals in ASCVD primary prevention in the Chinese population. Methods: We used data from 28,624 participants in the China Kadoorie Biobank (CKB) who had completed at least two field surveys. The risk assessment tools were the 10-year ASCVD risk prediction models developed based on the CKB cohort. We constructed multistate Markov models to model disease progression and estimate transition probabilities between different risk categories. The total person-years spent unidentified in the high-risk state over a 10-year period were calculated for each screening interval protocol. We also estimated the number of ASCVD events prevented, quality-adjusted life years (QALYs) gained, and costs saved when compared to the 3-yearly screening protocol. Findings: When compared to the uniform 3-yearly protocol, most risk-category-based screening interval protocols would identify more high-risk individuals timely, thus preventing more ASCVD events and gaining QALYs. A few of them would reduce total health-care costs. The protocol, which used 6-year, 3-year, and 2-year screening intervals for low-risk, intermediate-low-risk, and intermediate-high risk individuals, was optimal, and would reduce the person-years spent unidentified in the high-risk category by 17.9% (95% CI: 13.1%–21.9%), thus preventing an estimated 113 thousand (95% CI: 83–138) hard ASCVD events for Chinese adults aged 30–79 over a 10-year period. When using a lower cost of statin therapy, more screening protocols would gain QALYs while saving costs. Interpretation: For the primary prevention of ASCVD, risk-category-based screening protocols outperformed the one-size-fits-all approach in the Chinese population. Funding: This work was supported by National Natural Science Foundation of China (82192904, 82388102, 82192900) and grants (2023YFC2509400) from the National Key R&D Program of China. The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), grants (2016YFC0900500) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 91846303, 81941018), and Chinese Ministry of Science and Technology (2011BAI09B01).

Abstract Alcohol-related liver disease (ARLD) represents a major public health burden. Identification of high-risk individuals would allow efficient targeting of public health interventions. Here, we show significant interactions between pattern of drinking, genetic predisposition (polygenic risk score, PRS) and diabetes mellitus, and risk of incident ARLD, in 312,599 actively drinking adults in UK Biobank. Binge and heavy binge drinking significantly increase the risk of alcohol-related cirrhosis (ARC), with higher genetic predisposition further amplifying the risk. Further, we demonstrate a pronounced interaction between heavy binge drinking and high PRS, resulting in a relative excess risk due to interaction (RERI) of 6.07. Diabetes consistently elevates ARC risk across all drinking and PRS categories, and showed significant interaction with both binge patterns and genetic risk. Overall, we demonstrate synergistic effects of binge drinking, genetics, and diabetes on ARC, with potential to identify high-risk individuals for targeted interventions.

Prostate cancer is a heritable disease with ancestry-biased incidence and mortality. Polygenic risk scores (PRSs) offer promising advancements in predicting disease risk, including prostate cancer. While their accuracy continues to improve, research aimed at enhancing their effectiveness within African and Asian populations remains key for equitable use. Recent algorithmic developments for PRS derivation have resulted in improved pan-ancestral risk prediction for several diseases. In this study, we benchmark the predictive power of six widely used PRS derivation algorithms, including four of which adjust for ancestry, against prostate cancer cases and controls from the UK Biobank and All of Us cohorts. We find modest improvement in discriminatory ability when compared with a simple method that prioritizes variants, clumping, and published polygenic risk scores. Our findings underscore the importance of improving upon risk prediction algorithms and the sampling of diverse cohorts.

ObjectivesThe characteristics of multimorbidity in the Chinese population are currently unclear. We aimed to determine the temporal change in multimorbidity prevalence, clustering patterns, and the association of multimorbidity with mortality from all causes and four major chronic diseases.MethodsThis study analyzed data from the China Kadoorie Biobank study performed in Wuzhong District, Jiangsu Province. A total of 53,269 participants aged 30–79 years were recruited between 2004 and 2008. New diagnoses of 15 chronic diseases and death events were collected during the mean follow-up of 10.9 years. Yule's Q cluster analysis method was used to determine the clustering patterns of multimorbidity. A Cox proportional hazards model was used to estimate the associations of multimorbidity with mortalities.ResultsThe overall multimorbidity prevalence rate was 21.1% at baseline and 27.7% at the end of follow-up. Multimorbidity increased more rapidly during the follow-up in individuals who had a higher risk at baseline. Three main multimorbidity patterns were identified: (i) cardiometabolic multimorbidity (diabetes, coronary heart disease, stroke, and hypertension), (ii) respiratory multimorbidity (tuberculosis, asthma, and chronic obstructive pulmonary disease), and (iii) mental, kidney and arthritis multimorbidity (neurasthenia, psychiatric disorders, chronic kidney disease, and rheumatoid arthritis). There were 3,433 deaths during the follow-up. The mortality risk increased by 24% with each additional disease [hazard ratio (HR) = 1.24, 95% confidence interval (CI) = 1.20–1.29]. Compared with those without multimorbidity at baseline, both cardiometabolic multimorbidity and respiratory multimorbidity were associated with increased mortality from all causes and four major chronic diseases. Cardiometabolic multimorbidity was additionally associated with mortality from cardiovascular diseases and diabetes, with HRs of 2.64 (95% CI = 2.19–3.19) and 28.19 (95% CI = 14.85–53.51), respectively. Respiratory multimorbidity was associated with respiratory disease mortality, with an HR of 9.76 (95% CI = 6.22–15.31).ConclusionThe prevalence of multimorbidity has increased substantially over the past decade. This study has revealed that cardiometabolic multimorbidity and respiratory multimorbidity have significantly increased mortality rates. These findings indicate the need to consider high-risk populations and to provide local evidence for intervention strategies and health management in economically developed regions.

Summary: Background: Hospitals in China are classified into tiers (1, 2 or 3), with the largest (tier 3) having more equipment and specialist staff. Differential health insurance cost-sharing by hospital tier (lower deductibles and higher reimbursement rates in lower tiers) was introduced to reduce overcrowding in higher tier hospitals, promote use of lower tier hospitals, and limit escalating healthcare costs. However, little is known about the effects of differential cost-sharing in health insurance schemes on choice of hospital tiers. Methods: In a 9-year follow-up of a prospective study of 0.5 M adults from 10 areas in China, we examined the associations between differential health insurance cost-sharing and choice of hospital tiers for patients with a first hospitalisation for stroke or ischaemic heart disease (IHD) in 2009–2017. Analyses were performed separately in urban areas (stroke: n = 20,302; IHD: n = 19,283) and rural areas (stroke: n = 21,130; IHD: n = 17,890), using conditional logit models and adjusting for individual socioeconomic and health characteristics. Findings: About 64–68% of stroke and IHD cases in urban areas and 27–29% in rural areas chose tier 3 hospitals. In urban areas, higher reimbursement rates in each tier and lower tier 3 deductibles were associated with a greater likelihood of choosing their respective hospital tiers. In rural areas, the effects of cost-sharing were modest, suggesting a greater contribution of other factors. Higher socioeconomic status and greater disease severity were associated with a greater likelihood of seeking care in higher tier hospitals in urban and rural areas. Interpretation: Patient choice of hospital tiers for treatment of stroke and IHD in China was influenced by differential cost-sharing in urban areas, but not in rural areas. Further strategies are required to incentivise appropriate health seeking behaviour and promote more efficient hospital use. Funding: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and National Natural Science Foundation of China.

Summary: Background: China’s National Essential Public Health Service Package (NEPHSP) aims to promote health for all at the primary health care level and includes a focus on hypertension and type-2 diabetes mellitus (T2DM). However, there are limited contemporary data to quantify the care cascades of hypertension and T2DM in primary health care. Methods: This cross-sectional study involved individual level linkage of routinely collected data from the NEPHSP, health insurance claims and hospital electronic health records, from four diverse regions in China, including Xiling District (central China), Wenchuan County (western), Acheng District and Jiao District (northern). We first compared numbers of people aged ≥35 with a recorded diagnosis of hypertension and T2DM against expected numbers derived from epidemiological data. We then constructed care cascades to assess the percentages (1) enrolled in the NEPHSP, (2) adherent to the follow-up care of NEPHSP, (3) receiving medication treatment, and (4) having hypertension and/or T2DM controlled. Findings: In the four regions, the total numbers of people aged ≥35 diagnosed of hypertension and T2DM from any data source were 149,176 and 50,828, respectively. This was estimated to be 46.0% (95% confidence interval [CI]: 45.8%–46.2%) and 45.6% (95% CI: 45.3%–45.9%) of the expected totals for hypertension and T2DM, respectively. Among those diagnosed, 65.4% (95% CI: 65.1%–65.6%) with hypertension and 66.1% (95% CI: 65.7%–66.5%) with T2DM were enrolled in the NEPHSP, respectively, in which 54.8% (95% CI: 54.5%–55.2%) with hypertension and 64.7% (95% CI: 64.1%–65.2%) with T2DM were adherent to the required services. Among those enrolled, the overall treatment rates were 70.8% (95% CI: 70.6%–71.1%) for hypertension and 82.2% (95% CI: 81.8%–82.6%) for T2DM. Among those treated, a further 80.9% (95% CI: 80.6%–81.2%) with hypertension and 73.9% (95% CI: 73.3%–74.4%) with T2DM achieved control. These results varied considerably across regions, with the northern sites showing relatively higher enrolment rates while the central site had higher control rates. Interpretation: Detection and control rates for hypertension and T2DM are suboptimal in these four regions of China. Further strategies are needed to improve people’s enrolment in and adherence to the NEPHSP and strengthen care delivery processes. Of note, our estimations of the diagnosis rates for each region are based on national level large epidemiological data. The interpretation of these data needs caution due to potential bias caused by regional variations. Funding: This study is funded by National Health and Medical Research Council (NHMRC) Global Alliance for Chronic Diseases funding (APP1169757), and National Natural Science Foundation of China (72074065).

Summary: Background: Previous observational studies established a positive relationship between snoring and stroke. We aimed to investigate the causal effect of snoring on stroke. Methods: Based on 82,339 unrelated individuals with qualified genotyping data of Asian descent from the China Kadoorie Biobank (CKB), we conducted a Mendelian randomization (MR) analysis of snoring and stroke. Genetic variants identified in the genome-wide association analysis (GWAS) of snoring in CKB and UK Biobank (UKB) were selected for constructing genetic risk scores (GRS). A two-stage method was applied to estimate the associations of the genetically predicted snoring with stroke and its subtypes. Besides, MR analysis among the non-obese group (body mass index, BMI

Abstract Background Movement behaviours, including physical activity, sedentary behaviour, and sleep have been shown to be associated with several chronic diseases. However, they have not been objectively measured in large-scale prospective cohort studies in low-and middle-income countries. We aim to describe the patterns of device-measured movement behaviours collected in the China Kadoorie Biobank (CKB) study. Methods During 2020 and 2021, a random subset of 25,087 surviving CKB individuals participated in the 3rd resurvey of the CKB. Among them, 22,511 (89.7%) agreed to wear an Axivity AX3 wrist-worn triaxial accelerometer for seven consecutive days to assess their habitual movement behaviours. We developed a machine-learning model to infer time spent in four movement behaviours [i.e. sleep, sedentary behaviour, light intensity physical activity (LIPA), and moderate-to-vigorous physical activity (MVPA)]. Descriptive analyses were performed for wear-time compliance and patterns of movement behaviours by different participant characteristics. Results Data from 21,897 participants (aged 65.4 ± 9.1 years; 35.4% men) were received for demographic and wear-time analysis, with a median wear-time of 6.9 days (IQR: 6.1–7.0). Among them, 20,370 eligible participants were included in movement behavior analyses. On average, they had 31.1 mg/day (total acceleration) overall activity level, accumulated 7.7 h/day (32.3%) of sleep time, 8.8 h/day (36.6%) sedentary, 5.7 h/day (23.9%) in light physical activity, and 104.4 min/day (7.2%) in moderate-to-vigorous physical activity. There was an inverse relationship between age and overall acceleration with an observed decline of 5.4 mg/day (17.4%) per additional decade. Women showed a higher activity level than men (32.3 vs 28.8 mg/day) and there was a marked geographical disparity in the overall activity level and time allocation. Conclusions This is the first large-scale accelerometer data collected among Chinese adults, which provides rich and comprehensive information about device-measured movement behaviour patterns. This resource will enhance our knowledge about the potential relevance of different movement behaviours for chronic disease in Chinese adults.

Abstract Background Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. Methods We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. Results We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). Conclusion This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.

Abstract. Background:. Existing evidence suggests that fruit consumption is a significant influencing factor for chronic obstructive pulmonary disease (COPD), but this is unclear in the Chinese population. We examined the association of fresh fruit consumption with the risk of COPD-related hospitalization and death in a nationwide, population-based prospective cohort from China. Methods:. Between 2004 and 2008, the China Kadoorie Biobank recruited >0.5 million adults aged 30 to 79 years from ten diverse regions across China. After excluding individuals diagnosed with major chronic diseases and prevalent COPD, the prospective analysis included 421,428 participants. Cox regression was used to calculate the hazard ratios (HRs) for the association between fresh fruit consumption and risk of COPD-related hospitalization and death, with adjustment for established and potential confounders. Results:. During a mean follow-up of 10.9 years, 11,292 COPD hospitalization events and deaths were documented, with an overall incidence rate of 2.47/1000 person-years. Participants who consumed fresh fruit daily had a 22% lower risk of COPD-related hospitalization and death compared with non-consumers (HR = 0.78, 95% confidence interval [CI]: 0.71–0.87). The inverse association between fresh fruit consumption and COPD-related hospitalization and death was stronger among non-current smokers and participants with normal body mass index (BMI) (18.5 kg/m2 ≤ BMI < 24.0 kg/m2); the corresponding HRs for daily fresh fruit consumption were 0.78 (95% CI: 0.68–0.89) and 0.69 (95% CI: 0.59–0.79) compared with their counterparts, respectively. Conclusions:. High-frequency fruit consumption was associated with a lower risk of COPD in Chinese adults. Increasing fruit consumption, together with cigarette cessation and weight control, should be considered in the prevention and management of COPD.

Abstract. Background:. Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. Methods:. Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training (n = 28,490) and testing sets (n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. Results:. In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. Conclusions:. In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.

Abstract Background There is uncertainty about the optimum sleep duration for risk of different subtypes of stroke and ischaemic heart disease. Methods The present analyses involved 409,156 adults in the China Kadoorie Biobank study without a prior history of coronary heart disease or stroke or insomnia symptoms. The mean age of study participants was 52 years and 59% were women. Self-reported sleep duration including daytime napping was recorded using a questionnaire. The adjusted hazard ratios (HRs) for disease outcomes associated with sleep duration were estimated by Cox proportional hazards after adjustment for confounding factors. Results The overall mean (SD) sleep duration was 7.4 (1.4) hours. The associations of sleep duration with CVD types were U-shaped, with individuals reporting 7–8 h of sleep having the lowest risks. Compared with those who typically slept 7–8 h, individuals with very short sleep duration (≤ 5 h) had adjusted HRs of 1.10 (95% CI 1.04–1.16), 1.07 (1.01–1.13), 1.19 (1.06–1.33) and 1.23 (1.10–1.37) for total stroke, ischaemic stroke (IS), Intracerebral haemorrhage (ICH) and major coronary events (MCE), respectively. Likewise, individuals with very long sleep duration (≥ 10 h) had HRs of 1.12 (1.07–1.17), 1.08 (1.03–1.14), 1.23 (1.12–1.35) and 1.22 (1.10–1.34) for the same diseases, respectively, with little differences by sex and age. The patterns were similar for all-cause mortality. Conclusions While abnormal sleep duration (≤ 6 h or ≥ 9 h) was associated with higher risks of CVD, the risks were more extreme for those reporting ≤ 5 or ≥ 10 h, respectively and such individuals should be prioritised for more intensive treatment for CVD prevention.

Abstract Background In studies of the association of adiposity with disease risk, widely used anthropometric measures of adiposity (e.g. body-mass-index [BMI], waist circumference [WC], waist-hip ratio [WHR]) are simple and inexpensive to implement at scale. In contrast, imaging-based techniques (e.g. magnetic resonance imaging [MRI] and dual x-ray absorptiometry [DXA]) are expensive and labour intensive, but can provide more accurate quantification of body fat composition. There is, however, limited evidence about the relationship between conventional and imaging-derived measures of adiposity. Methods We searched Scopus and Web of Science for published reports in English of conventional versus imaging-derived measurements of adiposity. We identified 42 articles (MRI = 22; DXA = 20) that met selection criteria, involving 42,556 (MRI = 15,130; DXA = 27,426) individuals recruited from community or hospital settings. Study-specific correlation coefficients (r) were transformed using Fisher’s Z transformation, and meta-analysed to yield weighted average correlations, both overall and by ancestry, sex and age, where feasible. Publication bias was investigated using funnel plots and Egger’s test. Results Overall, 98% of participants were 18 + years old, 85% male and 95% White. BMI and WC were most strongly correlated with imaging-derived total abdominal (MRI-derived: r = 0.88-; DXA-derived: 0.50–0.86) and subcutaneous abdominal fat (MRI-derived: 0.83–0.85), but were less strongly correlated with visceral abdominal fat (MRI-derived: 0.76-0.79; DXA-derived: 0.80) and with DXA-derived %body fat (0.76). WHR was, at best, strongly correlated with imaging-derived total abdominal (MRI-derived: 0.60; DXA-derived: 0.13), and visceral abdominal fat (MRI-derived: 0.67; DXA-derived: 0.65), and moderately with subcutaneous abdominal (MRI-derived: 0.54), and with DXA-derived %body fat (0.58). All conventional adiposity measures were at best moderately correlated with hepatic fat (MRI-derived: 0.36–0.43). In general, correlations were stronger in women than in men, in Whites than in non-Whites, and in those aged 18 + years. Conclusions In this meta-analysis, BMI and WC, but not WHR, were very strongly correlated with imaging-derived total and subcutaneous abdominal fat. By comparison, all three measures were moderately or strongly correlated with imaging-based visceral abdominal fat, with WC showing the greatest correlation. No anthropometric measure was substantially correlated with hepatic fat. Further larger studies are needed to compare these measures within the same study population, and to assess their relevance for disease risks in diverse populations.

Furin is an important proteolytic enzyme, converting several proteins from inactive precursors to their active forms. Recently, proteo-genomic analyses in European and East Asian populations suggested a causal association of furin with ischaemic heart disease, and there is growing interest in its role in cardiovascular disease (CVD) aetiology. In this narrative review, we present a critical appraisal of evidence from population studies to assess furin’s role in CVD risk and potential as a drug target for CVD. Whilst most observational studies report positive associations between furin expression and CVD risk, some studies report opposing effects, which may reflect the complex biological roles of furin and its substrates. Genetic variation in FURIN is also associated with CVD and its risk factors. We found no evidence of current clinical development of furin as a drug target for CVD, although several phase 1 and 2 clinical trials of furin inhibitors as a type of cancer immunotherapy have been completed. The growing field of proteo-genomics in large-scale population studies may inform the future development of furin and other potential drug targets to improve the treatment and prevention of CVD.

Abstract. Background:. Severe liver disease (SLD), including cirrhosis and liver cancer, constitutes a major disease burden in China. We aimed to examine the association of genetic and healthy lifestyle factors with the incidence and prognosis of SLD. Methods:. The study population included 504,009 participants from the prospective China Kadoorie Biobank aged 30-79 years. The individuals were from 10 diverse areas in China without a history of cancer or liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HRs) for incident SLD and death after SLD diagnosis associated with healthy lifestyle factors (smoking, alcohol, physical activity, and central adiposity). Additionally, the contribution of genetic risk for hepatitis B virus (HBV, assessed by genetic variants in major histocompatibility complex, class II, DP/DQ [HLA-DP/DQ] genes) was also estimated. Results:. Compared with those with 0-1 healthy lifestyle factor, participants with 2, 3, and 4 factors had 12% (HR 0.88 [95% confidence interval [CI] 0.85, 0.92]), 26% (HR 0.74 [95%CI: 0.69, 0.79]), and 44% (HR 0.56 [95%CI: 0.48, 0.65]) lower risks of SLD, respectively. Inverse associations were observed among participants with both low and high genetic risks (HR per 1-point increase 0.83 [95%CI: 0.74, 0.94] and 0.91 [95%CI: 0.82, 1.02], respectively; Pinteraction = 0.51), although with a non-significant trend among those with a high genetic risk. Inverse associations were also observed between healthy lifestyle factors and liver biomarkers regardless of the genetic risk. Despite the limited power, healthy lifestyle factors were associated with a lower risk of death after incident SLD among participants with a low genetic risk (HR 0.59 [95%CI: 0.37, 0.96]). Conclusions:. Lifestyle modification may be beneficial in terms of lowering the risk of SLD regardless of the genetic risk. Moreover, it is also important for improving the prognosis of SLD in individuals with a low genetic risk. Future studies are warranted to examine the impact of healthy lifestyles on SLD prognosis, particularly among individuals with a high genetic risk.

Abstract Background Most lung cancer risk prediction models were developed in European and North‐American cohorts of smokers aged ≥ 55 years, while less is known about risk profiles in Asia, especially for never smokers or individuals aged < 50 years. Hence, we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range. Methods Based on the China Kadoorie Biobank cohort, we first systematically selected the predictors and explored the nonlinear association of predictors with lung cancer risk using restricted cubic splines. Then, we separately developed risk prediction models to construct a lung cancer risk score (LCRS) in 159,715 ever smokers and 336,526 never smokers. The LCRS was further validated in an independent cohort over a median follow‐up of 13.6 years, consisting of 14,153 never smokers and 5,890 ever smokers. Results A total of 13 and 9 routinely available predictors were identified for ever and never smokers, respectively. Of these predictors, cigarettes per day and quit years showed nonlinear associations with lung cancer risk (Pnon‐linear < 0.001). The curve of lung cancer incidence increased rapidly above 20 cigarettes per day and then was relatively flat until approximately 30 cigarettes per day. We also observed that lung cancer risk declined sharply within the first 5 years of quitting, and then continued to decrease but at a slower rate in the subsequent years. The 6‐year area under the receiver operating curve for the ever and never smokers’ models were respectively 0.778 and 0.733 in the derivation cohort, and 0.774 and 0.759 in the validation cohort. In the validation cohort, the 10‐year cumulative incidence of lung cancer was 0.39% and 2.57% for ever smokers with low (< 166.2) and intermediate‐high LCRS (≥ 166.2), respectively. Never smokers with a high LCRS (≥ 21.2) had a higher 10‐year cumulative incidence rate than those with a low LCRS (< 21.2; 1.05% vs. 0.22%). An online risk evaluation tool (LCKEY; http://ccra.njmu.edu.cn/lckey/web) was developed to facilitate the use of LCRS. Conclusions The LCRS can be an effective risk assessment tool designed for ever and never smokers aged 30 to 80 years.

Abstract Previous studies have linked higher body mass index (BMI) to lower subjective well-being in adult European ancestry populations. However, our understanding of these relationships across different populations is limited. Here, we investigated the association between BMI and well-being in people of (a) East Asian and (b) European ancestry in the China Kadoorie Biobank (CKB) and UK Biobank (UKB), respectively. Mendelian randomisation (MR) methods were used to test the relationship between BMI with (a) health satisfaction and (b) life satisfaction. One-sample MR enabled us to test effects in men and women separately and to test the role of cultural contexts by stratifying our analyses by urban and rural home location in both China and the UK. Further, we implemented a control function method to test the linearity of the BMI-well-being relationship. We found evidence of different associations between BMI and well-being in individuals of East Asian versus European ancestry. For example, a genetically instrumented higher BMI tentatively associated with higher health satisfaction in people of East Asian ancestry, especially in females (ß: 0.041, 95% CI: 0.002, 0.081). In contrast, there was a robust inverse association between higher genetically instrumented BMI and health satisfaction in all European ancestry UKB participants (ß: −0.183, 95% CI: −0.200, −0.165, P difference

Abstract Background The association of incident cardiometabolic multimorbidity (CMM) with mortality risk is rarely studied, and neither are the durations of cardiometabolic diseases (CMDs). Whether the association patterns of CMD durations with mortality change as individuals progress from one CMD to CMM is unclear. Methods Data from China Kadoorie Biobank of 512,720 participants aged 30–79 was used. CMM was defined as the simultaneous presence of two or more CMDs of interest, including diabetes, ischemic heart disease, and stroke. Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the duration-dependent associations of CMDs and CMM with all-cause and cause-specific mortality. All information on exposures of interest was updated during follow-up. Results During a median follow-up of 12.1 years, 99,770 participants experienced at least one incident CMD, and 56,549 deaths were documented. Among 463,178 participants free of three CMDs at baseline, compared with no CMD during follow-up, the adjusted HRs (95% CIs) between CMM and all-cause mortality, mortality from circulatory system diseases, respiratory system diseases, cancer, and other causes were 2.93 (2.80–3.07), 5.05 (4.74–5.37), 2.72 (2.35–3.14), 1.30 (1.16–1.45), and 2.30 (2.02–2.61), respectively. All CMDs exhibited a high mortality risk in the first year of diagnosis. Subsequently, with prolonged disease duration, mortality risk increased for diabetes, decreased for IHD, and sustained at a high level for stroke. With the presence of CMM, the above association estimates inflated, but the pattern of which remained. Conclusion Among Chinese adults, mortality risk increased with the number of the CMDs and changed with prolonged disease duration, the patterns of which varied among the three CMDs.

BackgroundMaternal smoking during pregnancy (MSDP) is a known risk factor for offspring developing chronic obstructive pulmonary disease (COPD), but the underlying mechanism remains unclear. ObjectiveThis study aimed to explore whether the increased COPD risk associated with MSDP could be attributed to tobacco dependence (TD). MethodsThis case-control study used data from the nationwide cross-sectional China Pulmonary Health study, with controls matched for age, sex, and smoking status. TD was defined as smoking within 30 minutes of waking, and the severity of TD was assessed using the Fagerstrom Test for Nicotine Dependence. COPD was diagnosed when the ratio of forced expiratory volume in 1 second to forced vital capacity was

Introduction Cohort evidence of the association of diabetes mellitus (DM) with chronic kidney disease (CKD) is limited. Previous studies often describe patients with kidney disease and diabetes as diabetic kidney disease (DKD) or CKD, ignoring other subtypes. The present study aimed to assess the prospective association of diabetes status (no diabetes, pre-diabetes, screened diabetes, previously diagnosed controlled/uncontrolled diabetes with/without antidiabetic treatment) and random plasma glucose (RPG) with CKD risk (including CKD subtypes) among Chinese adults.Research design and methods The present study included 472 545 participants from the China Kadoorie Biobank, using baseline information on diabetes and RPG. The incident CKD and its subtypes were collected through linkage with the national health insurance system during follow-up. Cox regression models were used to calculate the HR and 95% CI.Results During 11.8 years of mean follow-up, 5417 adults developed CKD. Screened plus previously diagnosed diabetes was positively associated with CKD (HR=4.52, 95% CI 4.23 to 4.83), DKD (HR=33.85, 95% CI 29.56 to 38.76), and glomerulonephritis (HR=1.66, 95% CI 1.40 to 1.97). In those with previously diagnosed diabetes, participants with uncontrolled diabetes represented higher risks of CKD, DKD, and glomerulonephritis compared with those with controlled RPG. The risk of DKD was found to rise in participants with pre-diabetes and increased with the elevated RPG level, even in those without diabetes.Conclusions Among Chinese adults, diabetes was positively associated with CKD, DKD, and glomerulonephritis. Screen-detected and uncontrolled DM had a high risk of CKD, and pre-diabetes was associated with a greater risk of DKD, highlighting the significance of lifelong glycemic management.

Summary: Background: Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. Methods: We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children 25 nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11–4.28), 7.61 (7.47–7.75) and 9.66 (9.52–9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. Interpretation: There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50–100% higher population mean plasma folate levels and 25–50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Funding: Medical Research Council (UK) and British Heart Foundation.

Abstract Background Effective risk prediction models are lacking for personalized endoscopic screening of gastric cancer (GC). We aimed to develop, validate, and evaluate a questionnaire-based GC risk assessment tool for risk prediction and stratification in the Chinese population. Methods In this three-stage multicenter study, we first selected eligible variables by Cox regression models and constructed a GC risk score (GCRS) based on regression coefficients in 416,343 subjects (aged 40–75 years) from the China Kadoorie Biobank (CKB, development cohort). In the same age range, we validated the GCRS effectiveness in 13,982 subjects from another independent Changzhou cohort (validation cohort) as well as in 5348 subjects from an endoscopy screening program in Yangzhou. Finally, we categorized participants into low (bottom 20%), intermediate (20–80%), and high risk (top 20%) groups by the GCRS distribution in the development cohort. Results The GCRS using 11 questionnaire-based variables demonstrated a Harrell’s C-index of 0.754 (95% CI, 0.745–0.762) and 0.736 (95% CI, 0.710–0.761) in the two cohorts, respectively. In the validation cohort, the 10-year risk was 0.34%, 1.05%, and 4.32% for individuals with a low (≤ 13.6), intermediate (13.7~30.6), and high (≥ 30.7) GCRS, respectively. In the endoscopic screening program, the detection rate of GC varied from 0.00% in low-GCRS individuals, 0.27% with intermediate GCRS, to 2.59% with high GCRS. A proportion of 81.6% of all GC cases was identified from the high-GCRS group, which represented 28.9% of all the screened participants. Conclusions The GCRS can be an effective risk assessment tool for tailored endoscopic screening of GC in China. Risk Evaluation for Stomach Cancer by Yourself (RESCUE), an online tool was developed to aid the use of GCRS.

Abstract. Background:. At present, a large number of chronic obstructive pulmonary disease (COPD) patients are undiagnosed in China. Thus, this study aimed to develop a simple prediction model as a screening tool to identify patients at risk for COPD. Methods:. The study was based on the data of 22,943 subjects aged 30 to 79 years and enrolled in the second resurvey of China Kadoorie Biobank during 2012 and 2013 in China. We stepwisely selected the predictors using logistic regression model. Then we tested the model validity through P–P graph, area under the receiver operating characteristic curve (AUROC), ten-fold cross validation and an external validation in a sample of 3492 individuals from the Enjoying Breathing Program in China. Results:. The final prediction model involved 14 independent variables, including age, sex, location (urban/rural), region, educational background, smoking status, smoking amount (pack-years), years of exposure to air pollution by cooking fuel, family history of COPD, history of tuberculosis, body mass index, shortness of breath, sputum and wheeze. The model showed an area under curve (AUC) of 0.72 (95% confidence interval [CI]: 0.72–0.73) for detecting undiagnosed COPD patients, with the cutoff of predicted probability of COPD=0.22, presenting a sensitivity of 70.13% and a specificity of 62.25%. The AUROC value for screening undiagnosed patients with clinically significant COPD was 0.68 (95% CI: 0.66–0.69). Moreover, the ten-fold cross validation reported an AUC of 0.72 (95% CI: 0.71–0.73), and the external validation presented an AUC of 0.69 (95% CI: 0.68–0.71). Conclusion:. This prediction model can serve as a first-stage screening tool for undiagnosed COPD patients in primary care settings.

Abstract Background DNA methylation clocks emerged as a tool to determine biological aging and have been related to mortality and age-related diseases. Little is known about the association of DNA methylation age (DNAm age) with coronary heart disease (CHD), especially in the Asian population. Results Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip for 491 incident CHD cases and 489 controls in the prospective China Kadoorie Biobank. We calculated the methylation age using a prediction model developed among Chinese. The correlation between chronological age and DNAm age was 0.90. DNA methylation age acceleration (Δage) was defined as the residual of regressing DNA methylation age on the chronological age. After adjustment for multiple risk factors of CHD and cell type proportion, compared with participants in the bottom quartile of Δage, the OR (95% CI) for CHD was 1.84 (1.17, 2.89) for participants in the top quartile. One SD increment in Δage was associated with 30% increased risk of CHD (OR = 1.30; 95% CI 1.09, 1.56; Ptrend = 0.003). The average number of cigarette equivalents consumed per day and waist-to-hip ratio were positively associated with Δage; red meat consumption was negatively associated with Δage, characterized by accelerated aging in those who never or rarely consumed red meat (all P

Abstract Background Existing evidence on long-term ambient air pollution (AAP) exposure and risk of cardio-respiratory diseases in China is mainly on mortality, and based on area average concentrations from fixed-site monitors for individual exposures. Substantial uncertainty persists, therefore, about the shape and strength of the relationship when assessed using more personalised individual exposure data. We aimed to examine the relationships between AAP exposure and risk of cardio-respiratory diseases using predicted local levels of AAP. Methods A prospective study included 50,407 participants aged 30–79 years from Suzhou, China, with concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), fine (PM2.5), and inhalable (PM10) particulate matter, ozone (O3) and carbon monoxide (CO) and incident cases of cardiovascular disease (CVD) (n = 2,563) and respiratory disease (n = 1,764) recorded during 2013–2015. Cox regression models with time-dependent covariates were used to estimate adjusted hazard ratios (HRs) for diseases associated with local-level concentrations of AAP exposure, estimated using Bayesian spatio–temporal modelling. Results The study period of 2013–2015 included a total of 135,199 person-years of follow-up for CVD. There was a positive association of AAP, particularly SO2 and O3, with risk of major cardiovascular and respiratory diseases. Each 10 µg/m3 increase in SO2 was associated with adjusted hazard ratios (HRs) of 1.07 (95% CI: 1.02, 1.12) for CVD, 1.25 (1.08, 1.44) for COPD and 1.12 (1.02, 1.23) for pneumonia. Similarly, each 10 µg/m3 increase in O3 was associated with adjusted HR of 1.02 (1.01, 1.03) for CVD, 1.03 (1.02, 1.05) for all stroke, and 1.04 (1.02, 1.06) for pneumonia. Conclusions Among adults in urban China, long-term exposure to ambient air pollution is associated with a higher risk of cardio-respiratory disease.

Abstract Background Extensive evidence links higher body mass index (BMI) to higher odds of depression in people of European ancestry. However, our understanding of the relationship across different settings and ancestries is limited. Here, we test the relationship between body composition and depression in people of East Asian ancestry. Methods Multiple Mendelian randomisation (MR) methods were used to test the relationship between (a) BMI and (b) waist-hip ratio (WHR) with depression. Firstly, we performed two-sample MR using genetic summary statistics from a recent genome-wide association study (GWAS) of depression (with 15,771 cases and 178,777 controls) in people of East Asian ancestry. We selected 838 single nucleotide polymorphisms (SNPs) correlated with BMI and 263 SNPs correlated with WHR as genetic instrumental variables to estimate the causal effect of BMI and WHR on depression using the inverse-variance weighted (IVW) method. We repeated these analyses stratifying by home location status: China versus UK or USA. Secondly, we performed one-sample MR in the China Kadoorie Biobank (CKB) in 100,377 participants. This allowed us to test the relationship separately in (a) males and females and (b) urban and rural dwellers. We also examined (c) the linearity of the BMI-depression relationship. Results Both MR analyses provided evidence that higher BMI was associated with lower odds of depression. For example, a genetically-instrumented 1-SD higher BMI in the CKB was associated with lower odds of depressive symptoms [OR: 0.77, 95% CI: 0.63, 0.95]. There was evidence of differences according to place of residence. Using the IVW method, higher BMI was associated with lower odds of depression in people of East Asian ancestry living in China but there was no evidence for an association in people of East Asian ancestry living in the USA or UK. Furthermore, higher genetic BMI was associated with differential effects in urban and rural dwellers within China. Conclusions This study provides the first MR evidence for an inverse relationship between BMI and depression in people of East Asian ancestry. This contrasts with previous findings in European populations and therefore the public health response to obesity and depression is likely to need to differ based on sociocultural factors for example, ancestry and place of residence. This highlights the importance of setting-specific causality when using genetic causal inference approaches and data from diverse populations to test hypotheses. This is especially important when the relationship tested is not purely biological and may involve sociocultural factors.

Abstract. Background:. Evidence on the relations of the American Heart Association's ideal cardiovascular health (ICH) with mortality in Asians is sparse, and the interaction between behavioral and medical metrics remained unclear. We aimed to fill the gaps. Methods:. A total of 198,164 participants without cancer and cardiovascular disease (CVD) were included from the China Kadoorie Biobank study (2004–2018), Dongfeng-Tongji cohort (2008–2018), and Kailuan study (2006–2019). Four behaviors (i.e., smoking, physical activity, diet, body mass index) and three medical factors (i.e., blood pressure, blood glucose, and blood lipid) were classified into poor, intermediate, and ideal levels (0, 1, and 2 points), which constituted 8-point behavioral, 6-point medical, and 14-point ICH scores. Results of Cox regression from three cohorts were pooled using random-effects models of meta-analysis. Results:. During about 2 million person-years, 20,176 deaths were recorded. After controlling for demographic characteristics and alcohol drinking, hazard ratios (95% confidence intervals) comparing ICH scores of 10–14 vs. 0–6 were 0.52 (0.41–0.67), 0.44 (0.37–0.53), 0.54 (0.45–0.66), and 0.86 (0.64–1.14) for all-cause, CVD, respiratory, and cancer mortality. A higher behavioral or medical score was independently associated with lower all-cause and CVD mortality among the total population and populations with different levels of behavioral or medical health equally, and no interaction was observed. Conclusions:. ICH was associated with lower all-cause, CVD, and respiratory mortality among Chinese adults. Both behavioral and medical health should be improved to prevent premature deaths.

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Abstract Background In China, the quantity of physical activity differs from that in Western countries. Substantial uncertainty remains about the relevance of physical activity for cancer subtypes among Chinese adults. Objective This study aimed to investigate the association between total daily physical activity and the incidence of common types of cancer. Methods A total of 53,269 participants aged 30–79 years were derived from the Wuzhong subcohort of the China Kadoorie Biobank study during 2004–2008. We included 52,938 cancer-free participants in the final analysis. Incident cancers were identified through linkage with the health insurance system and death registries. Cox proportional hazard models were introduced to assess the associations of total daily physical activity with the incidence of 6 common types of cancer. Results During a follow-up of 10.1 years, 3,674 cases of cancer were identified, including 794 (21.6%) from stomach cancer, 722 (19.7%) from lung cancer, 458 (12.5%) from colorectal cancer, 338 (9.2%) from liver cancer, 250 (6.8%) from breast cancer, and 231 (6.3%) from oesophageal cancer. Compared to the participants in the lowest quartile of physical activity levels, those in the highest quartile had an 11% lower risk for total cancer incidence (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.81–0.99), 25% lower risk for lung cancer incidence (HR: 0.75, 95% CI: 0.60–0.94), and 26% lower risk for colorectal cancer incidence (HR: 0.74, 95% CI: 0.55–1.00). There were significant interactions of physical activity with sex and smoking on total cancer (both P for interaction

Abstract Background Little is known about the effects of maintaining healthy sleep patterns on frailty transitions. Methods Based on 23,847 Chinese adults aged 30–79 in a prospective cohort study, we examined the associations between sleep patterns and frailty transitions. Healthy sleep patterns included sleep duration at 7 or 8 h/d, without insomnia disorder, and no snoring. Participants who persisted with a healthy sleep pattern in both surveys were defined as maintaining a healthy sleep pattern and scored one point. We used 27 phenotypes to construct a frailty index and defined three statuses: robust, prefrail, and frail. Frailty transitions were defined as the change of frailty status between the 2 surveys: improved, worsened, and remained. Log-binomial regression was used to calculate the prevalence ratio (PR) to assess the effect of sleep patterns on frailty transitions. Results During a median follow-up of 8.0 years among 23,847 adults, 45.5% of robust participants, and 10.8% of prefrail participants worsened their frailty status, while 18.6% of prefrail participants improved. Among robust participants at baseline, individuals who maintained sleep duration of 7 or 8 h/ds, without insomnia disorder, and no-snoring were less likely to worsen their frailty status; the corresponding PRs (95% CIs) were 0.92 (0.89–0.96), 0.76 (0.74–0.77), and 0.85 (0.82–0.88), respectively. Similar results were observed among prefrail participants maintaining healthy sleep patterns. Maintaining healthy sleep duration and without snoring, also raised the probability of improving the frailty status; the corresponding PRs were 1.09 (1.00–1.18) and 1.42 (1.31–1.54), respectively. Besides, a dose-response relationship was observed between constantly healthy sleep scores and the risk of frailty transitions (P for trend

Abstract Background In China, colorectal cancer (CRC) incidence and mortality have been steadily increasing over the last decades. Risk models to predict incident CRC have been developed in various populations, but they have not been systematically externally validated in a Chinese population. This study aimed to assess the performance of risk scores in predicting CRC using the China Kadoorie Biobank (CKB), one of the largest and geographically diverse prospective cohort studies in China. Methods Nine models were externally validated in 512,415 participants in CKB and included 2976 cases of CRC. Model discrimination was assessed, overall and by sex, age, site, and geographic location, using the area under the receiver operating characteristic curve (AUC). Model discrimination of these nine models was compared to a model using age alone. Calibration was assessed for five models, and they were re-calibrated in CKB. Results The three models with the highest discrimination (Ma (Cox model) AUC 0.70 [95% CI 0.69–0.71]; Aleksandrova 0.70 [0.69–0.71]; Hong 0.69 [0.67–0.71]) included the variables age, smoking, and alcohol. These models performed significantly better than using a model based on age alone (AUC of 0.65 [95% CI 0.64–0.66]). Model discrimination was generally higher in younger participants, males, urban environments, and for colon cancer. The two models (Guo and Chen) developed in Chinese populations did not perform better than the others. Among the 10% of participants with the highest risk, the three best performing models identified 24–26% of participants that went on to develop CRC. Conclusions Several risk models based on easily obtainable demographic and modifiable lifestyle factor have good discrimination in a Chinese population. The three best performing models have a higher discrimination than using a model based on age alone.

Abstract Associations of circulating metabolic biomarkers with type 2 diabetes (T2D) and their added value for risk prediction are uncertain among Chinese adults. A case-cohort study included 882 T2D cases diagnosed during 8-years’ follow-up and a subcohort of 789 participants. NMR-metabolomic profiling quantified 225 plasma biomarkers in stored samples taken at recruitment into the study. Cox regression yielded adjusted hazard ratios (HRs) for T2D associated with individual biomarkers, with a set of biomarkers incorporated into an established T2D risk prediction model to assess improvement in discriminatory ability. Mean baseline BMI (SD) was higher in T2D cases than in the subcohort (25.7 [3.6] vs. 23.9 [3.6] kg/m2). Overall, 163 biomarkers were significantly and independently associated with T2D at false discovery rate (FDR) controlled p

Abstract Background Hypertension, a well-known risk factor, contributes to millions of deaths from cardiovascular and renal diseases worldwide. However, evidence on the association between frequency of dairy product consumption and hypertension is inconsistent. Methods The data for the present study are from the Tongxiang baseline dataset of the China Kadoorie Biobank prospective study. A total of 53,916 participants aged 30–79 years were included in the final analysis. Multivariable logistic regression was utilized to evaluate the association of dairy product consumption with hypertension, and multiple linear regression was conducted to assess the association of dairy product consumption with systolic and diastolic blood pressure. Results Of the 53,916 participants, 2.6% reported consuming dairy products weekly, and 44.4% had prevalent hypertension. After adjusting for socio-demographic status, lifestyle factors, BMI, waist circumference, sleep duration and snoring, when compared with participants who never consumed dairy products, the odds ratios (95% CI) for hypertension among those consuming dairy products less than once per week, and ≥ 1 time per week were 0.85 (0.77–0.95) and 0.74 (0.65–0.84), respectively. The corresponding odds ratios (95% CI) for men were 0.85 (0.71–1.02) and 0.75 (0.61–0.92), respectively (P trend = 0.001), and for women were 0.88 (0.76–1.01) and 0.77 (0.65–0.91), respectively. (P trend

Abstract To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53 R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.

Summary: Population-based genome-wide association studies (GWAS) normally require a large sample size, which can be labor intensive and costly. Recently, we reported a human induced pluripotent stem cell (hiPSC) array-based GWAS method, identifying NDUFA4 as a host factor for Zika virus (ZIKV) infection. In this study, we extended our analysis to trophectoderm cells, which constitute one of the major routes of mother-to-fetus transmission of ZIKV during pregnancy. We differentiated hiPSCs from various donors into trophectoderm cells. We then infected cells carrying loss of function mutations in NDUFA4, harboring risk versus non-risk alleles of SNPs (rs917172 and rs12386620) or having deletions in the NDUFA4 cis-regulatory region with ZIKV. We found that loss/reduction of NDUFA4 suppressed ZIKV infection in trophectoderm cells. This study validated our published hiPSC array-based system as a useful platform for GWAS and confirmed the role of NDUFA4 as a susceptibility locus for ZIKV in disease-relevant trophectoderm cells.