Background Large blood-based prospective studies can provide reliable assessment of the complex interplay of lifestyle, environmental and genetic factors as determinants of chronic disease. Methods The baseline survey of the China Kadoorie Biobank took place during 2004–08 in 10 geographically defined regions, with collection of questionnaire data, physical measurements and blood samples. Subsequently, a re-survey of 25 000 randomly selected participants was done (80% responded) using the same methods as in the baseline. All participants are being followed for cause-specific mortality and morbidity, and for any hospital admission through linkages with registries and health insurance (HI) databases. Results Overall, 512 891 adults aged 30–79 years were recruited, including 41% men, 56% from rural areas and mean age was 52 years. The prevalence of ever-regular smoking was 74% in men and 3% in women. The mean blood pressure was 132/79 mmHg in men and 130/77 mmHg in women. The mean body mass index (BMI) was 23.4 kg/m² in men and 23.8 kg/m² in women, with only 4% being obese (>30 kg/m²), and 3.2% being diabetic. Blood collection was successful in 99.98% and the mean delay from sample collection to processing was 10.6 h. For each of the main baseline variables, there is good reproducibility but large heterogeneity by age, sex and study area. By 1 January 2011, over 10 000 deaths had been recorded, with 91% of surviving participants already linked to HI databases. Conclusion This established large biobank will be a rich and powerful resource for investigating genetic and non-genetic causes of many common chronic diseases in the Chinese population.

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry^1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis³, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach⁴, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry⁵. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom drink). The prospective China Kadoorie Biobank enrolled 512 715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161 498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self-reported drinking patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology-ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake. 33% (69 897/210 205) of men reported drinking alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302 510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14 930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers. In contrast, although genotype-predicted mean male alcohol intake varied widely (from 4 to 256 g per week-ie, near zero to about four drinks per day), it did not have any U-shaped associations with risk. For stroke, genotype-predicted mean alcohol intake had a continuously positive log-linear association with risk, which was stronger for intracerebral haemorrhage (relative risk [RR] per 280 g per week 1·58, 95% CI 1·36-1·84, p<0·0001) than for ischaemic stroke (1·27, 1·13-1·43, p=0·0001). For myocardial infarction, however, genotype-predicted mean alcohol intake was not significantly associated with risk (RR per 280 g per week 0·96, 95% CI 0·78-1·18, p=0·69). Usual alcohol intake in current drinkers and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few drank and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction. Genetic epidemiology shows that the apparently protective effects of moderate alcohol intake against stroke are largely non-causal. Alcohol consumption uniformly increases blood pressure and stroke risk, and appears in this one study to have little net effect on the risk of myocardial infarction. Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust.

Aims : The potential difference in the impacts of lifestyle factors (LFs) on progression from healthy to first cardiometabolic disease (FCMD), subsequently to cardiometabolic multimorbidity (CMM), and further to death is unclear.Methods and results : We used data from the China Kadoorie Biobank of 461 047 adults aged 30–79 free of heart disease, stroke, and diabetes at baseline. Cardiometabolic multimorbidity was defined as the coexistence of two or three CMDs, including ischaemic heart disease (IHD), stroke, and type 2 diabetes (T2D). We used multi-state model to analyse the impacts of high-risk LFs (current smoking or quitting because of illness, current excessive alcohol drinking or quitting, poor diet, physical inactivity, and unhealthy body shape) on the progression of CMD. During a median follow-up of 11.2 years, 87 687 participants developed at least one CMD, 14 164 developed CMM, and 17 541 died afterwards. Five high-risk LFs played crucial but different roles in all transitions from healthy to FCMD, to CMM, and then to death. The hazard ratios (95% confidence intervals) per one-factor increase were 1.20 (1.19, 1.21) and 1.14 (1.11, 1.16) for transitions from healthy to FCMD, and from FCMD to CMM, and 1.21 (1.19, 1.23), 1.12 (1.10, 1.15), and 1.10 (1.06, 1.15) for mortality risk from healthy, FCMD, and CMM, respectively. When we further divided FCMDs into IHD, ischaemic stroke, haemorrhagic stroke, and T2D, we found that LFs played different roles in disease-specific transitions even within the same transition stage.Conclusion : Assuming causality exists, our findings emphasize the significance of integrating comprehensive lifestyle interventions into both health management and CMD management.

The prevalence of diabetes in China has more than quadrupled in recent decades, with an estimated 110 million adults having diabetes in 2010 and 490 million adults estimated to have prediabetes.^1-4 A previous study estimated that diabetes accounted for 5% to 7% of overall adult mortality or disability-adjusted life-years in China in 2010.⁵ However, such estimates were derived mainly from extrapolation of risk estimates from studies conducted in high-income countries where many patients with diabetes have reasonably good control of blood glucose and take cardiovascular-protective medications.^6-9 Previous studies of diabetes and mortality in China have been limited by small sample size, enrollment of participants many decades ago (when the prevalence of diabetes was relatively low), or restriction to local occupational or urban cohorts.^10-12

Chinese men now smoke more than a third of the world's cigarettes, following a large increase in urban then rural usage. Conversely, Chinese women now smoke far less than in previous generations. We assess the oppositely changing effects of tobacco on male and female mortality. Two nationwide prospective studies 15 years apart recruited 220,000 men in about 1991 at ages 40-79 years (first study) and 210,000 men and 300,000 women in about 2006 at ages 35-74 years (second study), with follow-up during 1991-99 (mid-year 1995) and 2006-14 (mid-year 2010), respectively. Cox regression yielded sex-specific adjusted mortality rate ratios (RRs) comparing smokers (including any who had stopped because of illness, but not the other ex-smokers, who are described as having stopped by choice) versus never-smokers. Two-thirds of the men smoked; there was little dependence of male smoking prevalence on age, but many smokers had not smoked cigarettes throughout adult life. Comparing men born before and since 1950, in the older generation, the age at which smoking had started was later and, particularly in rural areas, lifelong exclusive cigarette use was less common than in the younger generation. Comparing male mortality RRs in the first study (mid-year 1995) versus those in the second study (mid-year 2010), the proportional excess risk among smokers (RR-1) approximately doubled over this 15-year period (urban: RR 1·32 [95% CI 1·24-1·41] vs 1·65 [1·53-1·79]; rural: RR 1·13 [1·09-1·17] vs 1·22 [1·16-1·29]), as did the smoking-attributed fraction of deaths at ages 40-79 years (urban: 17% vs 26%; rural: 9% vs 14%). In the second study, urban male smokers who had started before age 20 years (which is now typical among both urban and rural young men) had twice the never-smoker mortality rate (RR 1·98, 1·79-2·19, approaching Western RRs), with substantial excess mortality from chronic obstructive pulmonary disease (COPD RR 9·09, 5·11-16·15), lung cancer (RR 3·78, 2·78-5·14), and ischaemic stroke or ischaemic heart disease (combined RR 2·03, 1·66-2·47). Ex-smokers who had stopped by choice (only 3% of ever-smokers in 1991, but 9% in 2006) had little smoking-attributed risk more than 10 years after stopping. Among Chinese women, however, there has been a tenfold intergenerational reduction in smoking uptake rates. In the second study, among women born in the 1930s, 1940s, 1950s, and since 1960 the proportions who had smoked were, respectively, 10%, 5%, 2%, and 1% (3097/30,943, 3265/62,246, 2339/97,344, and 1068/111,933). The smoker versus non-smoker RR of 1·51 (1·40-1·63) for all female mortality at ages 40-79 years accounted for 5%, 3%, 1%, and <1%, respectively, of all the female deaths in these four successive birth cohorts. In 2010, smoking caused about 1 million (840,000 male, 130,000 female) deaths in China. Smoking will cause about 20% of all adult male deaths in China during the 2010s. The tobacco-attributed proportion is increasing in men, but low, and decreasing, in women. Although overall adult mortality rates are falling, as the adult population of China grows and the proportion of male deaths due to smoking increases, the annual number of deaths in China that are caused by tobacco will rise from about 1 million in 2010 to 2 million in 2030 and 3 million in 2050, unless there is widespread cessation. Wellcome Trust, MRC, BHF, CR-UK, Kadoorie Charitable Foundation, Chinese MoST and NSFC.