Genotyping and population characteristics of the China Kadoorie Biobank.

The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 from 10 geographically diverse regions across China. Detailed data from questionnaires and physical measurements were collected at baseline, with additional measurements at three resurveys involving ∼5% of surviving participants. Analyses of genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, and signatures reflecting large-scale population movements from recent Chinese history. Systematic genome-wide association studies of incident disease, captured through electronic linkage to death and disease registries and to the national health insurance system, replicate established disease loci and identify 14 novel disease associations. Together with studies of candidate drug targets and disease risk factors and contributions to international genetics consortia, these demonstrate the breadth, depth, and quality of the CKB data. Ongoing high-throughput omics assays of collected biosamples and planned whole-genome sequencing will further enhance the scientific value of this biobank.

Long-term ambient air pollution exposure and cardio-respiratory disease in China: findings from a prospective cohort study.

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.

Heterogeneity in the diagnosis and prognosis of ischemic stroke subtypes: 9-year follow-up of 22,000 cases in Chinese adults.

BACKGROUND: Reliable classification of ischemic stroke (IS) etiological subtypes is required in research and clinical practice, but the predictive properties of these subtypes in population studies with incomplete investigations are poorly understood. AIMS: To compare the prognosis of etiologically classified IS subtypes and use machine learning (ML) to classify incompletely investigated IS cases. METHODS: In a 9-year follow-up of a prospective study of 512,726 Chinese adults, 22,216 incident IS cases, confirmed by clinical adjudication of medical records, were assigned subtypes using a modified Causative Classification System for Ischemic Stroke (CCS) (large artery atherosclerosis (LAA), small artery occlusion (SAO), cardioaortic embolism (CE), or undetermined etiology) and classified by CCS as "evident," "probable," or "possible" IS cases. For incompletely investigated IS cases where CCS yielded an undetermined etiology, an ML model was developed to predict IS subtypes from baseline risk factors and screening for cardioaortic sources of embolism. The 5-year risks of subsequent stroke and all-cause mortality (measured using cumulative incidence functions and 1 minus Kaplan-Meier estimates, respectively) for the ML-predicted IS subtypes were compared with etiologically classified IS subtypes. RESULTS: Among 7443 IS subtypes with evident or probable etiology, 66% had SAO, 32% had LAA, and 2% had CE, but proportions of SAO-to-LAA cases varied by regions in China. CE had the highest rates of subsequent stroke and mortality (43.5% and 40.7%), followed by LAA (43.2% and 17.4%) and SAO (38.1% and 11.1%), respectively. ML provided classifications for cases with undetermined etiology and incomplete clinical data (24% of all IS cases; n = 5276), with area under the curves (AUC) of 0.99 (0.99-1.00) for CE, 0.67 (0.64-0.70) for LAA, and 0.70 (0.67-0.73) for SAO for unseen cases. ML-predicted IS subtypes yielded comparable subsequent stroke and all-cause mortality rates to the etiologically classified IS subtypes. CONCLUSION: This study highlighted substantial heterogeneity in prognosis of IS subtypes and utility of ML approaches for classification of IS cases with incomplete clinical investigations.

Association between involuntary smoking and risk of cervical cancer in Chinese female never smokers: A prospective cohort study.

Involuntary smoking was a major public health problem for women in China. Previous studies mainly focused on secondhand smoke (SHS), which referred to direct exposure to smoke from burning cigarettes. Little evidence existed about the relationship between thirdhand smoke (THS), the residual tobacco smoke remaining in the environment after tobacco had been smoked, and cervical cancer. The China Kadoorie Biobank (CKB) study recruited 0.3 million female participants from 10 areas across China during 2004-2008. After an 11.2-year median follow-up, we documented 1094 cervical cancer cases. Multivariable Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of SHS and THS with cervical cancer incidence, respectively and jointly. Overall, 60.3% reported weekly SHS exposure, and 83.2% had been exposed to THS. Daily SHS exposure and THS exposure at the enrollment were associated with elevated risks of cervical cancer incidence, with adjusted HRs (95% CI) of 1.22 (1.06,1.42) and 1.24 (1.03,1.49), respectively. The longer the exposure duration, the higher the risks (P for trend = 0.006, 0.035, respectively). Compared with those who were neither exposed to SHS nor THS, those exposed to both SHS and THS had the highest risk, with adjusted HRs (95% CI) of 1.29 (1.05,1.58). Area of residence, breastfeeding duration and heating fuel types are potential effect modifiers. Among Chinese females, both SHS and THS were associated with higher risks of cervical cancer incidence, and a dose-response relationship was found between the exposure duration and cervical cancer risk. Our findings reinforce the need for proactive strategies for tobacco control, to protect women health.

Low-risk Lifestyle and Health Factors and Risk of Mortality and Vascular Complications in Chinese Patients With Diabetes.

BACKGROUND: There is an evidence gap about whether a low-risk lifestyle is as important as achieving blood pressure (BP) and random blood glucose (RBG) control. OBJECTIVES: To explore the long-term impacts and relative importance of low-risk lifestyle and health factors on the risk of all-cause and cancer mortality and macrovascular and microvascular complications among patients with diabetes. METHODS: This study included 26,004 diabetes patients in the China Kadoorie Biobank. We defined 5 lifestyle factors (smoking, alcohol drinking, physical activity, fruit and vegetable intake, and waist-to-hip ratio) and 2 health factors (BP and RBG). Cox regression was used to yield adjusted hazard ratios (HRs) and CIs for individual and combined lifestyle and health factors with the risks of diabetes-related outcomes. RESULTS: There were 5063 deaths, 6848 macrovascular complications, and 2055 microvascular complications that occurred during a median follow-up of 10.2 years. Combined low-risk lifestyle factors were associated with lower risk of all main outcomes, with HRs (95% CIs) for participants having 4 to 5 low-risk factors vs 0 to 1 of 0.50 (0.44-0.57) for all-cause mortality, 0.55 (0.43-0.71) for cancer mortality, 0.60 (0.54-0.67) for macrovascular complications, and 0.75 (0.62-0.91) for microvascular complications. The combined 4 to 5 low-risk lifestyle factors showed relative importance in predicting all-cause and cancer mortality and macrovascular complications. CONCLUSIONS: Assuming causality exists, our findings suggest that adopting a low-risk lifestyle should be regarded as important as achieving ideal BP and glycemic goals in the prevention and management of diabetes-related adverse outcomes.

The hospitalization burden of all-cause pneumonia in China: A population-based study, 2009-2017.

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. :, ., .:(China Kadoorie Biobank)2004-2008555030-79.506,086200911.20091120171231.,30,.:8.9, 27,879, 36,567.8.4 (95% CI:8.3, 8.6)/1000, ,, 20094.2 (3.9, 4.4)201710.9 (10.6, 11.3), 15.5%.8.8(95% CI:8.7, 8.9), 1.0%.30, 2.4(95% CI:2.2, 2.5)/100.;,, 30.:, ≥60.

Diagnostic accuracy of major stroke types in Chinese adults: A clinical adjudication study involving 40,000 stroke cases.

Background: Widespread use of brain imaging in suspected stroke cases in Chinese adults has prompted the need for clinical adjudication studies of stroke types. We conducted a clinical adjudication study to assess the reporting and diagnostic accuracy of major stroke types. Methods: The prospective China Kadoorie Biobank recruited >512,000 adults (mean age 52 years, 59% women) from 10 urban and rural areas in China during 2004-2008, and recorded 45,859 first-ever incident stroke cases during an 11-year follow-up. Medical records were retrieved in ∼85%, and clinical details were recorded using a handheld computer for specialist physician adjudicators who applied conventional WHO clinical criteria for diagnosis of stroke. The positive predictive value (PPV) for reported and adjudicated stroke cases was examined for major stroke types (ischaemic stroke [IS], intracerebral haemorrhage [ICH], subarachnoid haemorrhage [SAH]), calendar year, area, and hospital type. Findings: Of 38,823 cases with retrieved medical records, the PPV for reported strokes was 91%. Among 29,952 adjudicated cases, the PPV for adjudicated cases was 81%, with higher PPV for ICH (n = 3391; 98%) and SAH (364; 98%) than for IS (20,473; 79%). Of 5504 cases with a verified IS diagnosis that was refuted on adjudication, 3763 (68%) had silent lacunar infarcts (LACI). The proportion of cases with silent LACI increased from 7.1% in 2004-2008 to 18.2% in 2016-2017. If cases with silent LACI were classified as IS, as advocated by new International Classification of Diseases (ICD-11) diagnostic criteria for stroke involving imaging and clinical rather than clinical criteria alone, the PPV increased to 93%. Interpretation: While the overall reporting and diagnostic accuracy of stroke types in Chinese adults is high, the recent implementation of new diagnostic criteria for IS has important implications for contemporary clinical practice and research on stroke in Chinese populations. Funding: Kadoorie Charitable Foundation, Hong Kong, China, UK Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), Chinese National Natural Science Foundation (91843302), and the National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904). British Heart Foundation, and UK Medical Research Council, and Cancer Research UK.

Alcohol metabolism genes and risks of site-specific cancers in Chinese adults: An 11-year prospective study.

Two genetic variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984, can modify oesophageal cancer risk associated with alcohol consumption in East Asians, but their associations with other cancers remain uncertain. ALDH2-rs671 G>A and ADH1B-rs1229984 G>A were genotyped in 150 722 adults, enrolled from 10 areas in China during 2004 to 2008. After 11 years' follow-up, 9339 individuals developed cancer. Cox regression was used to estimate hazard ratios (HRs) for site-specific cancers associated with these genotypes, and their potential interactions with alcohol consumption. Overall, the A-allele frequency was 0.21 for ALDH2-rs671 and 0.69 for ADH1B-rs1229984, with A-alleles strongly associated with lower alcohol consumption. Among men, ALDH2-rs671 AA genotype was associated with HR of 0.69 (95% confidence interval: 0.53-0.90) for IARC alcohol-related cancers (n = 1900), compared to GG genotype. For ADH1B-rs1229984, the HRs of AG and AA vs GG genotype were 0.80 (0.69-0.93) and 0.75 (0.64-0.87) for IARC alcohol-related cancers, 0.61 (0.39-0.96) and 0.61 (0.39-0.94) for head and neck cancer (n = 196) and 0.68 (0.53-0.88) and 0.60 (0.46-0.78) for oesophageal cancer (n = 546). There were no significant associations of these genotypes with risks of liver (n = 651), colorectal (n = 556), stomach (n = 725) or lung (n = 1135) cancers. Among male drinkers, the risks associated with higher alcohol consumption were greater among ALDH2-rs671 AG than GG carriers for head and neck, oesophageal and lung cancers (Pinteraction < .02). Among women, only 2% drank alcohol regularly, with no comparable associations observed between genotype and cancer. These findings support the causal effects of alcohol consumption on upper aerodigestive tract cancers, with ALDH2-rs671 AG genotype further exacerbating the risks.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.

Importance: Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). Objective: To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. Design, Setting, and Participants: This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Exposures: Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Main Outcomes and Measures: Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Results: Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). Conclusions and Relevance: CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2 METHODS: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. RESULTS: PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) = 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. CONCLUSIONS: Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.