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Abstract Objective Socioeconomic status (SES) has been proven to be associated with chronic obstructive pulmonary disease (COPD) in Western populations, but the evidence is very limited in China. This study aimed to investigate the association between SES and the risk of COPD incident. Methods This study was based on the China Kadoorie Biobank (CKB) project in Wuzhong District, Suzhou. A total of 45,484 adults aged 30–79 were included in the analysis during 2004–2008. We used Cox proportional hazard models to investigate the association between SES and the risk of COPD. Household income, education, private property and consumption potential was used to measure SES. Incident COPD cases were ascertained using hospitalization records, death certificates, and active follow-up. Results A total of 524 COPD cases were identified during a median follow-up of 11.2 years. Household income was inversely associated with the risk of COPD (P trend

Abstract Background Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks. Methods We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs. Results Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks. Conclusions For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks.

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 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: 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.

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.

Abstract Background Studies examining the relationships of stressful life events and cancer yielded inconsistent findings, while relevant evidence in mainland China is scarce. The current study sought to determine whether experience of stressful life events was associated with cancer prevalence in Chinese population. Methods We used cross-sectional data from the China Kadoorie Biobank study which that recruited 0.5 million Chinese adults aged 30 to 79 from 2004 to 2008. Logistic regression models were used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for cancer associated with stressful life events reported at baseline. Results Among the 461,696 participants included in this analysis, 2,122 (0.46%) had self-reported cancer with the mean (SD) age was 57.12 (9.71) years. Compared to those without any stressful life event, participants who experienced 1 and 2 or more events had significantly higher odds of cancer, with the ORs of 1.80 (95% CI: 1.58–2.05) and 3.05 (2.18–4.28). For categories of work-, family-, and personal-related events, the OR of cancer was 1.48 (1.07–2.05), 2.06 (1.80–2.35), and 1.65 (1.17–2.33), respectively. Regarding the specific stressful life events, loss of income/living on debt, major conflict within family, death/major illness of other close family member, and major injury/traffic accident were significantly associated with increased odds of cancer, with the ORs of 2.64 (1.81–3.86), 1.73 (1.20–2.50), 2.36 (2.05–2.72), and 2.11 (1.43–3.13). Conclusion Our findings suggested that experiences of cumulative and specific stressful life events were significantly associated with increased cancer prevalence in Chinese population.

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:. 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.

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

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.

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.

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

BackgroundChina has the largest burden of esophageal cancer (EC). Prediction models can be used to identify high-risk individuals for intensive lifestyle interventions and endoscopy screening. However, the current prediction models are limited by small sample size and a lack of external validation, and none of them can be embedded into the booming electronic health records (EHRs) in China. ObjectiveThis study aims to develop and validate absolute risk prediction models for EC in the Chinese population. In particular, we assessed whether models that contain only EHR-available predictors performed well. MethodsA prospective cohort recruiting 510,145 participants free of cancer from both high EC-risk and low EC-risk areas in China was used to develop EC models. Another prospective cohort of 18,441 participants was used for validation. A flexible parametric model was used to develop a 10-year absolute risk model by considering the competing risks (full model). The full model was then abbreviated by keeping only EHR-available predictors. We internally and externally validated the models by using the area under the receiver operating characteristic curve (AUC) and calibration plots and compared them based on classification measures. ResultsDuring a median of 11.1 years of follow-up, we observed 2550 EC incident cases. The models consisted of age, sex, regional EC-risk level (high-risk areas: 2 study regions; low-risk areas: 8 regions), education, family history of cancer (simple model), smoking, alcohol use, BMI (intermediate model), physical activity, hot tea consumption, and fresh fruit consumption (full model). The performance was only slightly compromised after the abbreviation. The simple and intermediate models showed good calibration and excellent discriminating ability with AUCs (95% CIs) of 0.822 (0.783-0.861) and 0.830 (0.792-0.867) in the external validation and 0.871 (0.858-0.884) and 0.879 (0.867-0.892) in the internal validation, respectively. ConclusionsThree nested 10-year EC absolute risk prediction models for Chinese adults aged 30-79 years were developed and validated, which may be particularly useful for populations in low EC-risk areas. Even the simple model with only 5 predictors available from EHRs had excellent discrimination and good calibration, indicating its potential for broader use in tailored EC prevention. The simple and intermediate models have the potential to be widely used for both primary and secondary prevention of EC.

Background The temporal relationship between type 2 diabetes (T2DM) and left ventricular hypertrophy (LVH) is not well established. This study aims to examine the temporal sequence between T2DM and LVH/cardiac geometry patterns in middle‐aged adults. Methods and Results The longitudinal cohort consisted of 1000 adults (682 White individuals and 318 Black individuals; 41.1% men; mean age, 36.2 years at baseline) who had data on fasting glucose/T2DM, left ventricular mass index (LVMI), and relative wall thickness collected twice at baseline and follow‐up over 9.4 years on average. The cross‐lagged path analysis model in 905 adults who did not take antidiabetic medications and the longitudinal prediction model in 1000 adults were used to examine the temporal relationships of glucose/T2DM with LVMI, LVH, relative wall thickness, and remodeling patterns. After adjustment for age, race, sex, smoking, alcohol drinking, body mass index, heart rate, hypertension, and follow‐up years, the path coefficient from baseline LVMI to follow‐up glucose was 0.088 (P=0.005); the path from baseline glucose to follow‐up LVMI was −0.009 (P=0.758). The 2 paths between glucose and relative wall thickness were not significant. The path analysis parameters did not differ significantly between race, sex, and follow‐up duration subgroups. Incidence of T2DM was higher in the baseline LVH group than in the normal LVMI group (24.8% versus 8.8%; P=0.017 for difference). Incidence of LVH and concentric LVH was higher in the baseline T2DM group than in the group without T2DM (50.0% versus 18.2% for LVH [P=0.005 for difference]; 41.7% versus 12.6% for concentric LVH [P=0.004 for difference]), with adjustment for covariates. Conclusions This study suggests that the temporal relationship between T2DM and LVH is likely bidirectional. The path from LVMI/LVH to glucose/T2DM is stronger than the path from glucose/T2DM to LVMI/LVH.

Summary: Background: The impact of solid fuel use on life expectancy (LE) in less-developed countries remains unclear. We aimed to evaluate the potential impact of household solid fuel use on LE in the rural and urban Chinese population, with the effect of smoking as a reference. Methods: We used data from China Kadoorie Biobank (CKB) of 484,915 participants aged 30–79 free of coronary heart disease, stroke, or cancer at baseline. Analyses were performed separately for solid fuel use for cooking, solid fuel use for heating, and smoking, with participants exposed to the other two sources excluded. Solid fuels refer to coal and wood, and clean fuels refer to electricity, gas, and central heating. We used a flexible parametric Royston-Parmar model to estimate hazard ratios of all-cause mortality and predict LE at age 30. Findings: Totally, 185,077, 95,228, and 230,995 participants were included in cooking-, heating-, and smoking-related analyses, respectively. During a median follow-up of approximately 12.1 years, 12,725, 7,531, and 18,878 deaths were recorded in the respective analysis. Compared with clean fuel users who reported cooking with ventilation, participants who used solid fuels with ventilation and without ventilation had a difference in LE (95% confidence interval [CI]) at age 30 of −1.72 (−2.88, −0.57) and −2.62 (−4.16, −1.05) years for men and −1.33 (−1.85, −0.81) and −1.35 (−2.02, −0.67) years for women, respectively. The difference in LE (95% CI) for heating was −2.23 (−3.51, −0.95) years for men and −1.28 (−2.08, −0.48) years for women. In rural men, the LE reduction (95% CI) related to solid fuel use for cooking (−2.55; −4.51, −0.58) or heating (−3.26; −6.09, 0.44) was more than that related to smoking (−1.71; −2.54, −0.89). Conversely, in urban men, the LE reduction (95% CI) related to smoking (−3.06; −3.56, −2.56) was more than that related to solid fuel use for cooking (−1.28; −2.61, 0.05) and heating (−1.90; −3.16, −0.65). Similar results were observed in women but with a smaller magnitude. Interpretation: In this Chinese population, the harm to LE from household use of solid fuels was greater than that from smoking in rural residents. Conversely, the negative impact of smoking was greater than solid fuel use in urban residents. Our findings highlight the complexity and diversity of the factors affecting LE in less-developed populations. Funding: National Natural Science Foundation of China, National Key R&D Program of China, Kadoorie Charitable Foundation, UK Wellcome Trust.

Summary: Background: This study aimed to: 1) assess the associations of biological age acceleration based on Klemera and Doubal's method (KDM-AA) with long-term risk of all-cause mortality; and 2) compare the association of KDM-AA with all-cause mortality among participants potentially at different stages of the cardiovascular disease (CVD) continuum. Methods: The present study was based on a subpopulation of the China Kadoorie Biobank, with baseline survey during 2004–08. A total of 12,377 participants free of ischemic heart disease, stroke, or cancer at baseline were included, in which 8180 participants were identified to develop major coronary event (MCE), ischemic stroke (IS), intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH), and 4197 remained free of these cardiovascular diseases before 1 January 2014. These participants were followed up until 1 Jan 2018. KDM-AA was calculated by regressing biological age measurement, which was constructed based on baseline 16 physical and 9 biochemical markers using Klemera and Doubal's method, on chronological age. We estimated the associations of KDM-AA with the mortality risk using the hazard ratio (HR) and 95% confidence interval (CI) from Cox proportional hazard models. We assessed discrimination performance by Harrell's C-index and net reclassification index (NRI). Findings: The participants who developed MCE (mean KDM-AA = 0.1 year, standard deviation [SD] = 1.6 years) or ICH/SAH (0.3 ± 1.5 years) during subsequent follow-up showed accelerated aging at baseline compared to those of IS (0.0 ± 1.2 years) and control (−0.3 ± 1.3 years) groups. The KDM-AA was positively associated with long-term risk of all-cause mortality (HR = 1.20; 95% CI: 1.17, 1.23), and the association was robust for participants potentially at different stages of the CVD continuum. Adding KDM-AA improved mortality prediction compared to the model only with sociodemographic and lifestyle factors in whole participants, with the Harrell's C-index increasing from 0.813 (0.807, 0.819) to 0.821 (0.815, 0.826) (NRI = 0.011; 95% CI: 0.003, 0.019). Interpretation: In this middle-aged and elderly Chinese population, the KDM-AA is a promising measurement for biological age, and can capture the difference in cardiovascular health and predict the risk of all-cause mortality over a decade. Funding: This work was supported by National Natural Science Foundation of China (82192904, 82192901, 82192900, 81941018). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation 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), and Chinese Ministry of Science and Technology (2011BAI09B01).

Summary: Background: Lower respiratory tract infections, including pneumonia, have been associated with short-term increased risk of cardiovascular disease (CVD). However, there is only limited evidence about the long-term impact of pneumonia on the cardiovascular system beyond one year. Methods: We conducted a prospective matched cohort study based on data from the China Kadoorie Biobank study of 482,017 adults who were enrolled between June 25, 2004, and July 15, 2008, and were free of CVD at baseline and before pneumonia hospitalization. A total of 24,060 patients hospitalised with pneumonia were identified until December 31, 2018, and were matched on age, sex, urban or rural areas, and decile of the frailty index to 223,875 controls. We used the piecewise Cox proportional hazards model to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for pre-specified incident CVD outcomes, including ischaemic heart disease (IHD), arrhythmia, heart failure (HF), ischaemic stroke (IS), and hemorrhagic stroke (HS), at various time intervals through 10 years after pneumonia hospitalization. Findings: Of the 247,935 pneumonia cases and controls included, the mean age (standard deviation) was 53.5 (10.4), and 40.8% (101,159) were men. During follow-up, 2389 (9.9%) pneumonia cases developed IHD, 489 (2.0%) cases developed arrhythmia, 545 (2.3%) cases developed HF, 1764 (7.3%) cases developed IS, and 348 (1.4%) cases developed HS. After adjustment for sociodemographic characteristics, lifestyle factors, health status and medication, underlying conditions, and family history of CVD, the elevated CVD risk was highest within the first 30 days after pneumonia hospitalisation, with subsequent risk reductions varying by subtypes. The elevated risk remained until the eighth year after pneumonia hospitalisation for IHD, arrhythmia, and HF, with HRs (95% CIs) of 1.48 (1.13–1.93), 2.69 (1.70–4.25), and 4.36 (2.86–6.64), respectively. The risk of stroke associated with pneumonia hospitalisation remained elevated until the seventh year for IS (HR = 1.30; 95% CI: 1.04–1.63), and until the second year for HS (1.39; 1.07–1.80). The above associations were consistently observed across various characteristics of the participants. Interpretation: In middle-aged and older Chinese adults, pneumonia hospitalisation was associated with short- and long-term CVD risk, with the elevated risk of certain CVD outcomes persisting for up to 8 years. Funding: National Natural Science Foundation of China, the National Key R&D Program of China, the Chinese Ministry of Science and Technology, the Kadoorie Charitable Foundation in Hong Kong, the UK Wellcome Trust.

Abstract. Background:. Few studies have assessed the relationship between multimorbidity patterns and mortality risk in the Chinese population. We aimed to identify multimorbidity patterns and examined the associations of multimorbidity patterns and the number of chronic diseases with the risk of mortality among Chinese middle-aged and older adults. Methods:. We used data from the China Kadoorie Biobank and included 512,723 participants aged 30 to 79 years. Multimorbidity was defined as the presence of two or more of the 15 chronic diseases collected by self-report or physical examination at baseline. Multimorbidity patterns were identified using hierarchical cluster analysis. Cox regression was used to estimate the associations of multimorbidity patterns and the number of chronic diseases with all-cause and cause-specific mortality. Results:. Overall, 15.8% of participants had multimorbidity. The prevalence of multimorbidity increased with age and was higher in urban than rural participants. Four multimorbidity patterns were identified, including cardiometabolic multimorbidity (diabetes, coronary heart disease, stroke, and hypertension), respiratory multimorbidity (tuberculosis, asthma, and chronic obstructive pulmonary disease), gastrointestinal and hepatorenal multimorbidity (gallstone disease, chronic kidney disease, cirrhosis, peptic ulcer, and cancer), and mental and arthritis multimorbidity (neurasthenia, psychiatric disorder, and rheumatoid arthritis). During a median of 10.8 years of follow-up, 49,371 deaths occurred. Compared with participants without multimorbidity, cardiometabolic multimorbidity (hazard ratios [HR] = 2.20, 95% confidence intervals [CI]: 2.14 − 2.26) and respiratory multimorbidity (HR = 2.13, 95% CI:1.97 − 2.31) demonstrated relatively higher risks of mortality, followed by gastrointestinal and hepatorenal multimorbidity (HR = 1.33, 95% CI:1.22 − 1.46). The mortality risk increased by 36% (HR = 1.36, 95% CI: 1.35 − 1.37) with every additional disease. Conclusion:. Cardiometabolic multimorbidity and respiratory multimorbidity posed the highest threat on mortality risk and deserved particular attention in Chinese adults.

Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.

Abstract Background Systemic studies of association of genome-wide DNA methylated sites with cardiovascular disease (CVD) in prospective cohorts are lacking. Our aim was to identify DNA methylation sites associated with the risk of CVD and further investigate their potential predictive value in CVD development for high-risk subjects. Methods We performed an epigenome-wide association study (EWAS) to identify CpGs related to CVD development in a Chinese population.We adopted a nested case–control design based on data from China PEACE Million Persons Project. A total of 83 cases who developed CVD events during follow-up and 83 controls who were matched with cases by age, sex, BMI, ethnicity, medications treatment and behavior risk factors were included in the discovery stage. Genome-wide DNA methylation from whole blood was detected using Infinium Human Methylation EPIC Beadchip (850 K). For significant CpGs [FDR(false discovery rate)

The prevalence of gestational diabetes mellitus (GDM) has increased with the increasing rate of obesity. However, national data on the prevalence and secular trends of GDM during the past decade in the United States are lacking. This study included 37,357 women aged more than 18 years and who had ever been pregnant from the National Health Interview Survey (NHIS). We examined GDM prevalence in 2006, 2016, and 2017, with age-standardized to the US population in 2000. We found that the prevalence of GDM per 100 people increased from 4.6 (95% CI, 4.1–5.1) in 2006 to 8.2 (95% CI, 7.5–8.9) in 2016 (test for difference; P

Summary: Background: Pneumonia represents a public health problem of substantial health and economic burden. However, the evidence on the burden of adult pneumonia is limited in China. Methods: The China Kadoorie Biobank recruited 512,725 participants aged 30–79 years from five urban and five rural areas during 2004–2008. The current analyses included 506,086 participants who were alive in 2009. Pneumonia hospitalizations were ascertained through the health insurance system until December 31, 2017. Generalized linear models were used to examine the secular trends and regional and population variations in pneumonia hospitalization rate, mean length of hospital stay (LOS), and 30-day case fatality rate (CFR). Findings: A total of 27,879 participants with 36,567 pneumonia hospitalizations were identified with a mean follow-up time of 8·9 years. The unadjusted hospitalization rate was 8·4 (95% confidence interval [CI]: 8·3, 8·6) per 1000 person-years, with an increase of 15·5% annually from 4·2 (3·9, 4·4) in 2009 to 10·9 (10·6, 11·3) in 2017, after adjusting for age, sex, study area. The mean LOS was 8·8 (95% CI: 8·7, 8·9) days, with a slight decrease of 1·0% annually from 2009 to 2017. The average 30-day CFR remained practically unchanged at 2·4 (95% CI: 2·2, 2·5) deaths per 100 admissions. A clear seasonal pattern of pneumonia hospitalization rate was observed, and the hospitalization rate and CFR differed across regions and subpopulations of different ages and underlying conditions. Interpretation: There was an increasing hospitalization burden of pneumonia in Chinese adults, especially for adults aged ≥60 years or those with underlying conditions. Funding: The National Natural Science Foundation of China, the Kadoorie Charitable Foundation, the National Key R&D Program of China, the Chinese Ministry of Science and Technology. Translated abstract in Chinese: This translation in Chinese was submitted by the authors and we reproduce it as supplied. It has not been peer reviewed. Our editorial processes have only been applied to the original abstract in English, which should serve as reference for this manuscript.摘要背景:肺炎是一个重要的公共卫生问题, 威胁人群健康的同时还造成沉重的经济负担.然而, 基于人群研究的中国成年人肺炎住院负担的研究证据十分有限.方法:中国慢性病前瞻性研究(China Kadoorie Biobank)于2004-2008年募集了来自5个城市和5个农村地区的50余万30-79岁的成年人.本研究纳入506,086名在2009年1月1日仍存活的研究对象.研究通过链接医保数据库获取研究对象2009年1月1日至2017年12月31日的肺炎住院数据.采用广义线性模型分析肺炎住院率,肺炎住院患者的住院时长及30天病死率的长期趋势及其地区,人群分布情况.结果:在平均8.9年的随访期内, 27,879名研究对象发生肺炎住院, 合计发生肺炎住院36,567人次.研究期间内肺炎的粗住院率为8.4 (95% CI:8.3, 8.6)/1000人年, 在调整年龄,性别和地区后, 由2009年的4.2 (3.9, 4.4)增长至2017年的10.9 (10.6, 11.3), 平均年增长率为15.5%.研究期间肺炎住院患者平均住院时长为8.8(95% CI:8.7, 8.9)天, 平均年缩短率为1.0%.肺炎住院患者的30天病死率没有明显改变, 研究期间粗病死率为2.4(95% CI:2.2, 2.5)/100例肺炎住院.本研究还发现肺炎住院率存在明显的季节性;不同地区,年龄和基础疾病的患者, 肺炎住院率和30天病死率都存在差异.解读:中国成年人中肺炎住院负担重且呈现增长趋势, 尤其是在≥60岁或存在基础疾病的研究对象中.

Abstract Background Chemerin is highly expressed in the serum, placenta tissue, and umbilical cord blood of diabetic mother; however, the impact of chemerin on cognitive disorders of offspring from mothers with diabetes in pregnancy remains unclear. Methods A diabetic phenotype in pregnant mice dams was induced by streptozocin (STZ) injection or intraperitoneal injection of chemerin. Behavioral changes in offspring of diabetic dams and nondiabetic controls were assessed, and changes in chemerin, two receptors of chemerin [chemerin receptor 23 (ChemR23) and chemokine (C-C motif) receptor-like 2 (CCRL2)], macrophages, and neurons in the brain tissue were studied to reveal the underlying mechanism of the behavioral changes. Results Chemerin treatment mimicked the STZ-induced symptom of maternal diabetes in mice along with the altered behavior of offspring in the open field test (OFT) assay. In the exploring process for potential mechanism, the brain tissues of offspring from chemerin-treated dams were observed with an increase level of macrophage infiltration and a decrease number of neuron cells. Moreover, an increased level of NOD-like receptor family pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like (Asc) protein as well as pyroptosis [characterized by increased active caspase-1 content and secretion of cytokines such as interleukin (IL) 1 beta (IL-1β) and IL-18] more activated in macrophages is also observed in the brain of these diabetic dam’s offspring, in the presence of ChemR23. In vitro, it was found that pyroptosis activation was increased in macrophages separated from the abdominal cavity of normal mice, after chemerin treatment. However, depletion of CCRL2 decreased the level of chemerin in the brain tissues of diabetic dams’ offspring; depletion of ChemR23 decreased macrophage pyroptosis, and depletion of either receptor reversed chemerin-mediated neurodevelopmental deficits and cognitive impairment of offspring of diabetic pregnant dams. Conclusions Chemerin induced diabetic pregnant disease and CCRL2 were required to enrich chemerin in the brain of offspring. Aggregation of chemerin could lead to macrophage recruitment, activation of pyroptosis, the release of inflammatory cytokines, a decrease in the number of neurons, and cognitive impairment in offspring in a ChemR23-dependent manner. Targeting CCRL2 and/or ChemR23 could be useful for treating neuropsychological deficits in offspring of dams with diabetes in pregnancy.

Aims/HypothesisWe aimed to explore whether and to what extent overweight or obesity could increase the risk of hypertension, and further to estimate the roles of genetic and early-life familial environmental factors in their association.MethodsThis prospective twin study was based on the Chinese National Twin Registry (CNTR), which collected information from self-report questionnaires. We conducted unmatched case-control analysis to examine the association between overweight or obesity and hypertension. And further to explore whether genetics and familiar environments shared within a twin pair, accounted for their association via co-twin matched case-control design. Generalized estimating equation (GEE) models and conditional logistic regressions were used in the unmatched and matched analyses, respectively. Then, we used logistic regressions to test the difference in odds ratios (ORs) between the unmatched and matched analyses. Finally, through bivariate twin model, the roles of genetic and environmental factors in the body mass index (BMI)- hypertension association were estimated.ResultsOverall, we included a total of 30,617 twin individuals, of which 7533 (24.6%) twin participants were overweight or obesity and 757 (2.5%) developed hypertension during a median follow-up time of 4.4 years. In the GEE model, overweight or obesity was associated with a 94% increased risk of hypertension (OR=1.94, 95% confidence interval (CI): 1.64~2.30). In the conditional logistic regression, the multi-adjusted OR was 1.80 (95% CI: 1.18~2.74). The difference in OR between unmatched and matched analyses was significant (P=0.016). Specifically, overweight or obesity was not associated with hypertension risk in the co-twin design when we full controlled genetic and familiar environmental factors (OR=0.89, 95 CI: 0.46~1.72). After controlling for age and sex, we found the positive BMI-hypertension association was mainly explained by a genetic correlation between them (rA= 0.59, 95% CI: 0.44~1.00).Conclusions/InterpretationGenetics and early-life environments shared by participants within a twin pair appear to account for the association between overweight or obesity and hypertension risk.

Background: The prevalence of obesity and cardiometabolic diseases continues to rise globally and obesity is a significant risk factor for cardiometabolic diseases. However, to our knowledge, evidence of the relative roles of genes and the environment underlying obesity and cardiometabolic disease traits and the correlations between them are still lacking, as is how they change with age. Method: Data were obtained from the Chinese National Twin Registry (CNTR). A total of 1421 twin pairs were included. Univariate structural equation models (SEMs) were performed to evaluate the heritability of BMI and cardiometabolic traits, which included blood hemoglobin A1c (HbA1c), fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Bivariate SEMs were used to assess the genetic/environmental correlations between them. The study population was divided into three groups for analysis: ≤50, 51–60, and >60 years old to assess the changes in heritability and genetic/environmental correlations with ageing. Results: Univariate SEMs showed a high heritability of BMI (72%) and cardiometabolic traits, which ranged from 30% (HbA1c) to 69% (HDL-C). With age increasing, the heritability of all phenotypes has different degrees of declining trends. Among these, BMI, SBP, and DBP presented significant monotonous declining trends. The bivariate SEMs indicated that BMI correlated with all cardiometabolic traits. The genetic correlations were estimated to range from 0.14 (BMI and LDL-C) to 0.39 (BMI and DBP), while the environmental correlations ranged from 0.13 (BMI and TC/LDL-C) to 0.31 (BMI and TG). The genetic contributions underlying the correlations between BMI and SBP and DBP, TC, TG, and HDL-C showed a progressive decrease as age groups increased. In contrast, environmental correlations displayed a significant increasing trend for HbA1c, SBP, and DBP. Conclusions: The findings suggest that genetic and environmental factors have essential effects on BMI and all cardiometabolic traits. However, as age groups increased, genetic influences presented varying degrees of decrement for BMI and most cardiometabolic traits, suggesting the increasing importance of environments. Genetic factors played a consistently larger role than environmental factors in the phenotypic correlations between BMI and cardiometabolic traits. Nevertheless, the relative magnitudes of genetic and environmental factors may change over time.

Background: Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population. Methods: We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10 year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module. Results: After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR < 0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47 % decrease to a 118 % increase. Mediation analyses revealed 28.5 % of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of ANKS1A gene (P for mediation effect = 0.036). Methylation level at the promoter region of SNX30 was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7 % (P = 0.003) via systolic blood pressure and 6.4 % (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD. Conclusions: We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and blood pressure-related pathways to CHD risk. Funding: This work was supported by National Natural Science Foundation of China (81390544 and 91846303). 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 (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).

It is unclear how the dietary patterns reflecting C-reactive protein (CRP) affect metabolic syndrome (MetS) in the Chinese population. To examine the effect of the dietary pattern reflecting CRP with MetS, a cross-sectional study was based on the health checkup data from the Beijing MJ Health Screening Centers between 2008 and 2018. The CRP-related dietary pattern was derived from 17 food groups using reduced-rank regression. Participants were divided into five groups according to the quintiles of dietary pattern score. Multivariate logistic regression was then applied to estimate the odds ratios (OR) and 95% confidence intervals (CIs) for the quintiles of diet pattern score related to MetS and its four components. Of the 90,130 participants included in this study, 11,209 had MetS. A CRP-related dietary pattern was derived, characterized by a higher consumption of staple food, fresh meat, processed products, and sugar-sweetened beverages but a lower intake of honey and jam, fruits, and dairy products. Compared with participants in the lowest quintile (Q1), participants in the higher quintiles were associated with increased risks of MetS in a dose–response manner after adjustment for potential confounders (p for linear trend < 0.001), the ORs for Q2 to Q5 were 1.10 (95% CI: 1.02–1.19), 1.14 (95% CI: 1.05–1.22), 1.23 (95% CI: 1.15–1.33), and 1.49 (95% CI: 1.38–1.61), respectively. Moreover, the effects were stronger among individuals aged 50 years or older. A CRP-related dietary pattern was associated with the risk of MetS. It provides new insights that dietary intervention to achieve a lower inflammatory level could potentially prevent MetS.

Objective. The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene (TCF7L2). We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obese adults in several randomized controlled trials (RCTs). Methods. From October 2016 to May 2018, a large collaborative analysis was performed by pooling individual-participant data from 7 RCTs. These RCTs reported changes in glycemic control and adiposity of the variant rs7903146 after dietary/lifestyle-related interventions in overweight or obese adults. Gene treatment interaction models which used the genetic effect encoded by the allele dose and common covariates were applicable to individual participant data in all studies. Results. In the joint analysis, a total of 7 eligible RCTs were included (n=4,114). Importantly, we observed a significant effect modification of diet/lifestyle-related interventions on the TCF7L2 variant rs7903146 and changes in fasting glucose. Compared with the control group, diet/lifestyle interventions were related to lower fasting glucose by -3.06 (95% CI, -5.77 to -0.36) mg/dL (test for heterogeneity and overall effect: I2=45.1%, p

Compelling evidence indicates that lipid metabolism is in partial control of the circadian system. In this context, it has been reported that the melatonin receptor 1B (MTNR1B) genetic variant influences the dynamics of melatonin secretion, which is involved in the circadian system as a chronobiotic. The objective was to analyze whether the MTNR1B rs10830963 genetic variant was related to changes in lipid levels in response to dietary interventions with different macronutrient distribution in 722 overweight/obese subjects from the POUNDS Lost trial. We did not find a significant association between the MTNR1B genotype and changes in lipid metabolism. However, dietary fat intake significantly modified genetic effects on 2 year changes in total and LDL cholesterol (P interaction = 0.006 and 0.001, respectively). In the low-fat diet group, carriers of the sleep disruption G allele (minor allele) showed a greater reduction of total cholesterol (β ± SE = −5.78 ± 2.88 mg/dl, P = 0.04) and LDL cholesterol (β ± SE = −7.19 ± 2.37 mg/dl, P = 0.003). Conversely, in the high-fat diet group, subjects carrying the G allele evidenced a smaller decrease in total cholesterol (β ± SE = 5.81 ± 2.65 mg/dl, P = 0.03) and LDL cholesterol (β ± SE = 5.23 ± 2.21 mg/dl, P = 0.002). Subjects carrying the G allele of the circadian rhythm-related MTNR1B variant may present a bigger impact on total and LDL cholesterol when undertaking an energy-restricted low-fat diet.

Abstract To explore novel molecular mechanisms underlying obesity, we applied a systems genetics framework to integrate risk genetic loci from the largest body mass index (BMI) genome-wide association studies (GWAS) meta-analysis with mRNA and microRNA profiling in adipose tissue from 200 subjects. One module was identified to be most significantly associated with obesity and other metabolic traits. We identified eight hub genes which likely play important roles in obesity metabolism and identified microRNAs that significantly negatively correlated with hub genes. This module was preserved in other three test gene expression datasets, and all hub genes were consistently downregulated in obese subjects through the meta-analysis. Gene GPD1L had the highest connectivity and was identified a key causal regulator in the module. Gene GPD1L was significantly negatively correlated with the expression of miR-210, which was experimentally validated that miR-210 regulated GPD1L protein level through direct interaction with its mRNA three prime untranslated region (3′-UTR). GPD1L was found to be upregulated during weight loss and weight maintenance induced by low calorie diet (LCD), while downregulated during weight gain induced by high-fat diet (HFD). The results indicated that increased GPD1L in adipose tissue may have a significant therapeutic potential in reducing obesity and insulin resistance.

In this study, we conducted an epigenome-wide association study of metabolic syndrome (MetS) among 846 participants of European descent in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). DNA was isolated from CD4+ T cells and methylation at ~470,000 cytosine-phosphate-guanine dinucleotide (CpG) pairs was assayed using the Illumina Infinium HumanMethylation450 BeadChip. We modeled the percentage methylation at individual CpGs as a function of MetS using linear mixed models. A Bonferroni-corrected P-value of 1.1 x 10(-7) was considered significant. Methylation at two CpG sites in CPT1A on chromosome 11 was significantly associated with MetS (P for cg00574958 = 2.6x10(-14) and P for cg17058475 = 1.2x10(-9)). Significant associations were replicated in both European and African ancestry participants of the Bogalusa Heart Study. Our findings suggest that methylation in CPT1A is a promising epigenetic marker for MetS risk which could become useful as a treatment target in the future.

Lifestyle factors are well-known important modifiable risk factors for obesity; the association between tobacco smoking and central obesity, however, is largely unknown in the Chinese population. This study examined the relationship between smoking and central obesity in 0.5 million Chinese adults, a population with a low prevalence of general obesity, but a high prevalence of central obesity.A total of 487,527 adults (200,564 males and 286,963 females), aged 30-79 years, were enrolled in the baseline survey of the China Kadoorie Biobank (CKB) Study conducted during 2004-2008. Waist circumference (WC) and WC/height ratio (WHtR) were used as measures of central obesity.The prevalence of regular smokers was significantly higher among males (60.6%) than among females (2.2%). The prevalence of central obesity increased with age and BMI levels, with a significant gender difference (females>males). Of note, almost all obese adults (99.4%) were centrally obese regardless of gender. In multivariable regression analyses, adjusting for age, education, physical activity, alcohol use and survey site, regular smoking was inversely associated with BMI in males (standardized regression coefficients, β= -0.093, p

Elevated serum uric acid (UA) is commonly found in subjects with metabolic syndrome (MetS). This study examined the association of UA with levels of individual MetS components and the degree of their clustering patterns in both children and adults.The study sample consisted of 2614 children aged 4-18 years and 2447 adults aged 19-54 years. MetS components included body mass index (BMI), mean arterial pressure (MAP), triglycerides to high-density lipoprotein cholesterol ratio (TG/HDLC), and homeostasis model assessment of insulin resistance (HOMA). Observed/expected (O/E) ratio and intra-class correlation coefficient (ICC) were used as a measure of the degree of clustering of categorical and continuous MetS variables, respectively.UA was positively and significantly associated only with BMI in children but with all four components in adults. The odds ratio for MetS associated with 1 mg/dL increase of UA was 1.74 (p

OBJECTIVE: To understand the changes of the nutrition labeling of packaged food in China two years after the promulgation of the Regulation for Food Nutrition Labeling, which encourages food manufacturers to identify nutrition labeling. METHODS: Investigators copied out the nutrition information panel, nutrition claim and nutrient function claim of packaged food in a supermarket with prepared questionnaire and finished normative judgment in 2008 and 2010. RESULTS: 4693 and 5526 kinds of packaged food were investigated separately. Nutrition information panel, nutrition claim and nutrient function claim were found on the food label of 27.6%, 13.0% and 1.9% of packaged food respectively in 2008, while 35.1%, 7.7% and 2.3% in 2010. The nutrition information panel which labeled energy, protein, fat, carbohydrate and sodium was 597 (43.8%) and 1661 (85.9%) in 2008 and 2010, only 134 (9.8%) and 985 (51.0%) nutrition information panel were totally normalized. Nutrition claim and nutrient function claim focused on vitamin, mineral and dietary fiber. The total qualified proportions for nutrition claim were increased significantly for most of the nutrients, except for cholesterol. There were 6 (6.4%) and 5 (3.9%) nutrient function claims with hinting of therapeutic effects on diseases separately. CONCLUSION: Although the voluntary regulation remarkably improved the level of normalization for nutrition labeling, its role on the prevalence was minus. It's imperative to enforce nutrition labeling for not only China but also other countries, and furthermore, health education on nutrition labeling should be initiated to support the policy.

Background and purpose Previous studies, mostly focusing on the European population, have reported polygenic risk scores (PRSs) might achieve risk stratification of stroke. We aimed to examine the association strengths of PRSs with risks of stroke and its subtypes in the Chinese population.Methods Participants with genome-wide genotypic data in China Kadoorie Biobank were split into a potential training set (n=22 191) and a population-based testing set (n=72 150). Four previously developed PRSs were included, and new PRSs for stroke and its subtypes were developed. The PRSs showing the strongest association with risks of stroke or its subtypes in the training set were further evaluated in the testing set. Cox proportional hazards regression models were used to estimate the association strengths of different PRSs with risks of stroke and its subtypes (ischaemic stroke (IS), intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH)).Results In the testing set, during 872 919 person-years of follow-up, 8514 incident stroke events were documented. The PRSs of any stroke (AS) and IS were both positively associated with risks of AS, IS and ICH (p