Associations with mortality of social inequalities, smoking and drinking differ widely between populations. Here we recruited 500,810 adults aged ≥35 years from Chennai city during 1998–2001 in South India and followed to 2020 for verbal-autopsy-assessed cause-specific mortality. Among those initially without chronic disease, multivariable-adjusted Cox regression (censored at age 70 years) related initial characteristics to mortality rates. Even among non-smoking non-drinkers, those with no schooling had almost three times the mortality rate ratio (RR) of those with >11 years education (men, RR of 2.76, 95% confidence interval (CI) 2.58–2.95; women, RR of 2.93, 95% CI 2.69–3.19), with substantial mortality excesses from each major disease category. These social inequalities were further exacerbated by much higher smoking and drinking prevalences among less educated men. Adjusted for education, male smoking (versus not, RR of 1.26, 95% CI 1.22–1.29) and drinking (versus not, RR of 1.52, 95% CI 1.48–1.56) were independently associated with risk and together almost doubled male mortality (both versus neither, RR of 1.89, 95% CI 1.84–1.94). Few women (<0.1%) smoked or drank. A 20-year prospective cohort study of 458,609 adults in Chennai shows that educational disadvantage is associated with premature mortality even among non-smokers and non-drinkers, and in men, smoking and alcohol use amplify these social inequalities, with combined use nearly doubling mortality risk before age 70.

OBJECTIVE:The Mexican population experiences a notably high prevalence of type 2 diabetes (T2D) and high T2D-associated disease risks. We used targeted plasma nuclear magnetic resonance metabolomics data within a Mendelian randomization framework to characterize the metabolomic profile of genetically predicted liability to T2D in this population. RESEARCH DESIGN AND METHODS:Between 1998 and 2004, 50,000 men and 100,000 women aged ≥35 years were recruited from Mexico City. Mendelian randomization analyses used a genetic risk score (GRS) comprising 1,055 established T2D-associated risk variants and eight pathway-specific T2D GRSs constructed from nonoverlapping subsets of these variants to estimate associations with 143 metabolic biomarkers (including lipids, lipoproteins, fatty acids, amino acids, ketone bodies, and other low-molecular-weight biomarkers). RESULTS:Among 125,587 included participants, the T2D GRS explained 6.0% of T2D liability and was not associated with major potential confounders of the relationships of T2D with the circulating metabolome. Genetically predicted liability to T2D was strongly positively associated with concentrations of VLDL particles and lipids within these, with triglycerides, branched-chain amino acids, and glycoprotein acetyls, and more modestly positively associated with intermediate-density lipoprotein and LDL, particularly small LDL, particles. Inverse associations were found with relative concentrations of several fatty acids. Pathway-specific T2D GRSs all associated with higher T2D risk but showed differential relationships with circulating metabolic biomarkers. CONCLUSIONS:T2D is associated with widespread changes in the circulating metabolome among adults in Mexico, reflecting diverse biological mechanisms and highlighting the importance of effective T2D management, including control of T2D-associated dyslipidemia, in this population.

Background: Analyses of the 2014 EBCTCG database suggested that, in early-stage breast cancer, obesity was strongly independently associated with breast cancer mortality only in pre/peri-menopausal oestrogen-receptor-positive (ER+) disease (Pan et al ASCO 2014). Based on the far larger 2024 EBCTCG database, however, we can now test that unexpected finding and better characterise any relevance of patient characteristics to the association of body mass index (BMI) with distant recurrence and mortality. Methods: We analysed patient-level data on time to distant recurrence and death from the 206,904 women with early-stage breast cancer (entered during 1978-2017 into 147 randomised trials) in the 2024 EBCTCG database who had BMI at entry (within two years of diagnosis) recorded as 15-50 kg/m2 and with complete information on age, ER status, tumour diameter, nodal status, and randomly allocated treatment. Information on menopausal status, tumour grade, and HER2 status was available for most participants. Cox regression was used to estimate the associations of BMI with rates of distant recurrence and breast cancer mortality, calculating hazard rate ratios (RRs) per 5 kg/m2 increase of BMI or comparing 3 BMI groups (obese: BMI 30-50 [mean 34.7]; overweight: BMI 25 to <30 [mean 27.3]; lean: BMI 15 to <25 [mean 22.2] kg/m2). Results: Of the 206,904 women, 60% were postmenopausal at trial entry and 77% had ER+ disease. Their mean BMI was 27.1 (SD 5.6) kg/m2 and 26.0% (53,872) were obese (BMI ≥30 kg/m2). The prevalence of obesity increased from 19% in the early 1980s to 27% in the early 2010s. The overall adjusted rate ratio (RR) of first distant recurrence (ignoring any local or contralateral recurrences) was 1.06 (95% CI 1.05-1.07, p<0.0001) per 5 kg/m2 increase in BMI. The RR for overweight versus lean women was 1.07 (CI 1.04-1.10, p<0.0001), and that for obese versus lean women was 1.17 (95% CI 1.14-1.20, p<0.0001). This approximately log-linear association between BMI and the rate of distant recurrence was seen irrespective of patient or tumour characteristics, type of adjuvant systemic therapy, year of diagnosis, or time since diagnosis. In the 82,464 pre-menopausal women the RR per 5 kg/m2 increase of BMI was 1.08 (1.07-1.10, p<0.0001), and in the 124,440 post-menopausal women it was 1.05 (1.03-1.06, p<0.0001; heterogeneity between RRs p=0.0004). There was little heterogeneity between the RRs in ER+ and ER-poor disease. In the 159,119 women with ER+ disease the RR per 5 kg/m2 increase of BMI was 1.06 (1.05-1.08, p<0.0001), and in the 47,785 with ER-poor disease it was 1.06 (1.04-1.08, p<0.0001). The associations of BMI with breast cancer mortality mirrored those with distant recurrence. Conclusion: Overweight and obesity are associated with increased distant recurrence and breast cancer mortality in all types of patients with early-stage breast cancer, but the risk associated with a substantial (e.g. 5 kg/m2) difference in BMI is only moderate. Nevertheless, randomised assessment of the effects among overweight or obese women with early breast cancer of weight-loss interventions (perhaps utilising a GLP-1 receptor agonist) could usefully be added, using a factorial design, to some current and future adjuvant treatment trials addressing unrelated questions. Reference: Pan H, Gray R, on behalf of the EBCTCG. Effect of obesity in premenopausal ER+ early breast cancer: EBCTCG data on 80,000 patients in 70 trials. J Clin Oncol 2014; 32:5s Citation Format: Hongchao Pan, Richard Gray, Richard Peto, Jeremy Braybrooke, David Dodwell, Robert Hills, Rosie Bradley, Hellen Gelband, Hui Liu, Paul McGale, Carolyn Taylor, Mike Clarke, Wolfgang Janni, Marianne Ewertz, Pamela J Goodwin, Joseph Sparano, Kathy I Pritchard, Jonas Bergh, Sandra M Swain, for the Early Breast Cancer Trialists™ Collaborative Group (EBCTCG). Overweight, obesity and prognosis in 206,904 women in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) database [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-09.

BACKGROUND:Observational studies relating blood pressure in middle age to mortality may underestimate lifelong effects. Mendelian randomization can reduce the impact of confounding and reverse causality and may better estimate lifelong effects of blood pressure on mortality. METHODS:Mendelian randomization analyses used 125 895 Mexico City Prospective Study participants aged 35 to 74 years at recruitment with valid genetic and other data. Cox regression, adjusted for confounders and regression dilution bias, related blood pressure to mortality in 133 027 participants aged 35 to 74 years without prior chronic disease (other than diabetes) at recruitment. RESULTS:In the genetic analyses (40 560 [32%] men; mean age 50 years, mean body mass index 29 kg/m2) there were 13 153 deaths before age 75 years (3478 cardiovascular, 2053 kidney, and 7622 other). Each 10 mm Hg higher genetically predicted lifelong systolic blood pressure was associated with 73% higher cardiovascular mortality at ages 35 to 74 years (rate ratio, 1.73 [95% CI, 1.44-2.06]), 42% higher kidney death (1.42 [95% CI, 1.15-1.75]), but no clear increase in death from other causes. These lifelong rate ratios were higher than those estimated by observational analyses relating blood pressure in middle age to risk. Mendelian randomization analyses of lifelong diastolic blood pressure confirmed strong associations with cardiovascular but not kidney death. Mortality rate ratios were similar for men and women and in those with versus without diabetes, and broadly similar at different ages and at different proportions of Indigenous American ancestry. Sensitivity analyses gave consistent results. CONCLUSIONS:In this Mexican population, genetically informed lifelong differences in blood pressure were strongly related to death from cardiovascular and kidney disease.

Background:Observational epidemiological studies in Mexico have shown high mortality risks associated with type 2 diabetes (T2D). However, it is unclear whether these relationships are wholly causal. We aimed to assess the association of genetically-predicted T2D liability with risk of death in Mexico. Methods:Between 1998 and 2004, 150,000 men and women were recruited from Mexico City and followed-up until September 2022 for cause-specific mortality. Mendelian randomisation analyses, using a genetic risk score (GRS) comprising 1055 established T2D-associated risk variants, estimated associations with risk of all-cause and cause-specific mortality at ages 35-74. Findings:Among 121,433 included participants with a mean (standard deviation) age of 51 (11), 68% (n = 82,249) were women and 18% (n = 21,371) had T2D. The GRS explained 6.3% of T2D liability and was not associated with major potential confounders of the T2D-mortality relationship. During a median (interquartile range) of 20.2 (19.4-21.4) years' follow-up, 12,293 participants died. Genetically-predicted T2D liability was associated with a death rate ratio (RR) of 1.29 (95% confidence interval [CI] 1.23-1.36) per trebling in genetically-predicted odds of T2D. There were particularly strong associations with death from renal disease (n = 1696; RR 2.29 [95% CI 1.99-2.64]) and acute diabetic crises (n = 509; RR 2.27 [1.75-2.93]) and weaker, but still strong, associations with death from vascular disease (n = 3226; RR 1.31 [1.19-1.46]) and infection (n = 2437; RR 1.21 [1.07-1.36]). Genetically-predicted T2D liability was not clearly associated with death from cancer (n = 2016; RR 1.00 [95% CI 0.88-1.14]) or cirrhosis (n = 895; RR 0.90 [0.74-1.10]). Interpretation:T2D is causally associated with death from vascular, renal and infectious diseases. Its prevention and effective management could substantially reduce premature deaths in Mexico, where T2D is common. Funding:Wellcome Trust, the Mexican Health Ministry, the National Council for Science and Technology (CONACyT) for Mexico, Cancer Research UK, British Heart Foundation, Kidney Research UK, UK Medical Research Council, AstraZeneca, Regeneron.

BACKGROUND:Persistent hyperglycaemia in diabetes can cause weight loss, distorting the association of adiposity with mortality. We estimated the lifelong associations of genetically predicted body mass index (BMI) with 52 causes of death among 125 003 Mexican adults, in whom persistent hyperglycaemia in diabetes was common. METHODS:A trans-ancestry genetic instrument for BMI (from 724 BMI-associated single-nucleotide polymorphisms) estimated the causal relevance of BMI to mortality before age 75 years, stratified by sex and adjusted for age and underlying ancestry structure, using a one-sample Mendelian randomization (MR) approach. Two-sample MR and other sensitivity analyses were also performed. RESULTS:The genetic instrument explained 3% of the BMI variation and predicted BMI similarly in men and women. Each 5-kg/m2 higher genetically predicted BMI was associated with nearly a doubling in the risk of all-cause mortality at ages 35-74 years [13 066 deaths; hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.63-2.00]. Hazard ratios were greater for vascular-metabolic (n =  7111; HR 2.15, 95% CI 1.87-2.48) than for non-vascular-metabolic causes (n =  5955; HR 1.47, 95% CI 1.27-1.71) and particularly strong for renal (n =  2034; HR 3.59, 95% CI 2.76-4.67), acute diabetic crises (n =  557; HR 2.70, 95% CI 1.64-4.44), and infective deaths (n =  811; HR 2.61, 95% CI 1.73-3.92). For all-cause mortality, HRs were somewhat greater at younger ages compared with older ages, and slightly larger in those with a higher proportion of Indigenous American ancestry. The strength of the association with mortality was reduced by more than half after simple adjustment for genetic predisposition to diabetes. Sensitivity analyses supported the main conclusions. CONCLUSION:In this Mexican population, genetically predicted lifelong BMI was strongly related to mortality and mediated substantially through diabetes.

BACKGROUND:Smokers have lower body weight than non-smokers, while smoking cessation results in weight gain. Understanding the mechanisms involved can help identify potential therapeutic targets to enhance smoking cessation. METHODS:We measured plasma levels of growth/differentiation factor 15 (GDF15), a stress-responsive protein, and its two receptors (proto-oncogene tyrosine-protein kinase receptor Ret [RET], GDNF family receptor alpha-like [GFRAL]) among 3936 Chinese adults (mean BMI 24.0 kg/m2), using Olink and SomaScan platforms. We assessed associations of individual proteins and GDF15/receptor ratios with smoking and adiposity using linear regression. In two-sample Mendelian randomization (MR) analyses, we used genetic variants for smoking intensity from publicly available GWAS as instruments to assess their causal associations with adiposity and plasma levels of proteins in East Asian and European populations. We further assessed the effects of GDF15 and GDF15/receptor ratios in mediating smoking-related weight change. FINDINGS:Overall, smokers had significantly lower BMI (23.1 [0.2] kg/m2) than never-smokers (24.0 [0.1] kg/m2), while former smokers had the highest levels of BMI (24.6 [0.2] kg/m2) and other measures of adiposity (e.g., waist circumference, waist/hip ratio, and body fat percentage). In observational analyses, smoking was positively associated with GDF15 and with GDF15/receptor ratios from both platforms, with GDF15 levels increasing steeply with number of cigarettes smoked on the assessment day. In MR analyses, smoking intensity was significantly associated with a reduced BMI in East Asians and with higher GDF15 levels in both East Asian and European populations. SomaScan_GDF15 partially mediated the associations of smoking with all adiposity measures, while Olink_GDF15 mediated the association with body fat percentage. The GDF15/RET ratio more robustly mediated the smoking-adiposity relationships than GDF15 alone in both platforms. INTERPRETATION:In Chinese adults GDF15 plays a role in mediating smoking-related weight change, and could serve as a therapeutic target to facilitate smoking cessation and minimise cessation-induced weight gain. FUNDING:British Heart Foundation, Cancer Research UK, Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, UK Medical Research Council, National Natural Science Foundation of China, Wellcome Trust.

BACKGROUND:At the beginning of the 2018-2020 outbreak of Ebola virus disease (EVD) in eastern Democratic Republic of Congo (DRC), no vaccine had been licensed. However, cluster-randomized evidence from Guinea in 2015 had indicated that ring vaccination around new cases (targeting contacts and contacts-of-contacts) with the use of single-dose live-replicating rVSV-ZEBOV-GP vaccine reduced EVD rates starting 10 days after vaccination. Thus, ring vaccination was added to the standard control measures for that outbreak. METHODS:In this study, we evaluated the incidence of EVD within the first 9 days after vaccination (when little protection was expected from case isolation or ring vaccination), during days 10 to 29, and at later time periods. We established 1853 rings around new cases or clusters within 21 days after symptom onset in the index case and offered vaccination to the ring members. Vaccinees were monitored for EVD onset until the end of the outbreak in mid-2020. RESULTS:From August 8, 2018, to January 14, 2020, we vaccinated 265,183 participants. Of these vaccinees, 102,515 were monitored on days 0, 3, and 21 for safety. Among the contacts and contacts-of-contacts, 434 cases of EVD (0.2 per ring) were diagnosed, almost all within 0 to 9 days (380 cases) or 10 to 29 days (32 cases) after vaccination. An additional 22 cases were diagnosed after day 29 during an average of 170 more days of follow-up. The sooner that control measures (including ring vaccination) began after EVD onset in the index case, the sooner EVD rates fell among contacts. In each subgroup, EVD rates fell suddenly around day 10. Among the contacts and contacts-of-contacts who were still disease-free at day 10, the EVD onset rate during days 10 to 29 was 0.16 per 1000 (in 32 of 194,019 participants). This rate was much lower than the rate of 4.64 per 1000 (in 21 of 4528 participants) that had been seen among similarly defined ring members in Guinea, in whom standard control measures had been promptly initiated but vaccination was delayed until 21 days after ring formation (rate ratio, 0.04; 95% confidence interval, 0.02 to 0.06). No safety concerns with the vaccine were identified. CONCLUSIONS:Nonrandomized evidence regarding standard EVD control measures plus ring vaccination in eastern DRC reinforces the earlier randomized evidence from Guinea of vaccine efficacy against EVD onset 10 or more days after vaccination.

Background Although death in old age is unavoidable, premature death-defined here as death before age 70 years- is not. To assess whether halving premature mortality by 2050 is feasible, we examined the large variation in premature death rates before age 70 years and trends over the past 50 years (1970-2019), covering ten world regions and the 30 most-populous nations. This analysis was undertaken in conjunction with the third report of The Lancet Commission on Investing in Health: Global Health 2050: the path to halving premature death by mid-century. Methods In this cross-country analysis of past mortality trends and future directions, all analyses on the probability of premature death (PPD) were conducted using life tables from the UN World Population Prospects 2024. For each sex, country, and year, probability of death was calculated from these life tables with 1-year age-specific mortality rates. Findings Globally, PPD decreased from 56% in 1970 to 31% in 2019, although some countries saw reversals because of conflict, social instability, or HIV and AIDS. Child mortality has decreased faster than adult mortality. Among all countries, 34 halved their PPD over three decades between 1970 and 2019. Among the 30 most-populous countries, seven countries, with varying levels of baseline PPD and income, halved their PPD in the past half century. Seven of the most-populous countries had average annual rates of improvement in the period 2010-19 that, if sustained, could lead to a halving of PPD by 2050, including Korea (39%), Bangladesh (28%), Russia (27%), Ethiopia (24%), Iran (24%), South Africa (24%), and T & uuml;rkiye (23%). Interpretation Halving premature death by 2050 is feasible, although substantial investments in child and adult health are needed to sustain or accelerate the rate of improvement for high-performing and medium-performing countries. Particular attention must be paid to countries with very low or a worsening rate of improvement in PPD. By reducing premature mortality, more people will live longer and more healthy lives. However, as people live longer, the absolute number of years lived with chronic disease will increase and investments in services reducing chronic disease morbidity are needed. Funding The Norwegian Agency for Development Cooperation, the Bill & Melinda Gates Foundation, and a Norwegian Research Council Centre of Excellence grant. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY CC 4.0 license.

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

BACKGROUND:Alcohol consumption is a leading cause of premature death globally, but there is no large-scale prospective evidence from Mexico. METHODS:The Mexico City Prospective Study recruited 150 000 adults aged 35 years or older between 1998 and 2004. Participants were followed up until Oct 1, 2022 for cause-specific mortality. Cox regression in those with no self-reported chronic disease at entry (adjusted for age, sex, district, education, physical activity, smoking, and diabetes) was used to relate baseline-reported alcohol consumption (never, former, occasional [less than monthly], and regular [at least monthly, split into <70, ≥70 to <140, ≥140 to <210, and ≥210 g/week]) to mortality at ages 35-74 from all causes, and from a pre-specified alcohol-related set of underlying causes. Heavy episodic drinking (normally consuming >5 [men] or >4 [women] drinks on a single occasion) and type of preferred drink were also examined. FINDINGS:Among 138 413 participants aged 35-74 years at recruitment, 21 136 (15%) were regular alcohol drinkers (14 863 [33%] men, 6273 [7%] women), of whom 13 383 (63%) favoured spirits and 6580 (31%) favoured beer. During follow-up, there were 13 889 deaths at ages 35-74 years, including 3067 deaths from the pre-specified alcohol-related causes. Overall, J-shaped associations with mortality were observed. Compared with occasional drinkers, those with baseline-reported consumption ≥210 g/week had 43% higher all-cause mortality (rate ratio [RR] 1·43 [95% CI 1·30-1·56]) and nearly three times the mortality from the pre-specified alcohol-related causes (2·77 [2·39-3·20]). Death from liver disease was strongly related to alcohol consumption; the RR comparing regular drinkers of ≥140 g/week with occasional drinkers was 4·03 (3·36-4·83). Compared with occasional light drinking, occasional heavy episodic drinking was associated with 20% higher alcohol-related mortality (1·20 [1·06-1·35]), and regular heavy episodic drinking was associated with 89% higher alcohol-related mortality (1·89 [1·67-2·15]). Drinks with alcohol percentages higher than spirits were associated with the greatest increased mortality risk, even after accounting for the total alcohol consumed. INTERPRETATION:In this Mexican population, higher alcohol consumption, episodic drinking, and very high percentage alcoholic products were all associated with increased mortality. FUNDING:Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, and the UK Medical Research Council. TRANSLATION:For the Spanish translation of the abstract see Supplementary Materials section.

Plasma proteomics could enhance risk prediction for multiple diseases beyond conventional risk factors or polygenic scores (PS). To assess utility of proteomics for risk prediction of ischemic heart disease (IHD) compared with conventional risk factors and PS in Chinese and European populations. A nested case-cohort study measured plasma levels of 2923 proteins using Olink Explore panel in 4000 Chinese adults (1976 incident IHD cases and 2001 sub-cohort controls). We used conventional and machine learning (Boruta) methods to develop proteomics-based prediction models of IHD, with discrimination assessed using area under the curve (AUC), C-statistics and net reclassification index (NRI). These were compared with conventional risk factors and PS in Chinese and in 37,187 Europeans. Overall, 446 proteins were associated with IHD (false discovery rate < 0.05) in Chinese after adjustment for conventional cardiovascular disease risk factors. Proteomic risk models alone yielded higher C-statistics for IHD than conventional risk factors or PS (0.855 [95

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

BACKGROUND Integrated analyses of plasma proteomic and genetic markers in prospective studies can clarify the causal relevance of proteins and discover novel targets for ischemic heart disease (IHD) and other diseases.OBJECTIVES The purpose of this study was to examine associations of proteomics and genetics data with IHD in population studies to discover novel preventive treatments.METHODS We conducted a nested case-cohort study in the China Kadoorie Biobank (CKB) involving 1,971 incident IHD cases and 2,001 subcohort participants who were genotyped and free of prior cardiovascular disease. We measured 1,463 proteins in the stored baseline samples using the OLINK EXPLORE panel. Cox regression yielded adjusted HRs for IHD associated with individual proteins after accounting for multiple testing. Moreover, cis-protein quantitative loci (pQTLs) identified for proteins in genome-wide association studies of CKB and of UK Biobank were used as instrumental variables in separate 2-sample Mendelian randomization (MR) studies involving global CARDIOGRAM+C4D consortium (210,842 IHD cases and 1,378,170 controls).RESULTS Overall 361 proteins were significantly associated at false discovery rate <0.05 with risk of IHD (349 positively, 12 inversely) in CKB, including N-terminal prohormone of brain natriuretic peptide and proprotein convertase subtilisin/kexin type 9. Of these 361 proteins, 212 had cis-pQTLs in CKB, and MR analyses of 198 variants in CARDIO-GRAM+C4D identified 13 proteins that showed potentially causal associations with IHD. Independent MR analyses of 307 cis-pQTLs identified in Europeans replicated associations for 4 proteins (FURIN, proteinase-activated receptor-1, Asia-loglycoprotein receptor-1, and matrix metalloproteinase-3). Further downstream analyses showed that FURIN, which is highly expressed in endothelial cells, is a potential novel target and matrix metalloproteinase-3 a potential repurposing target for IHD. CONCLUSIONS Integrated analyses of proteomic and genetic data in Chinese and European adults provided causal support for FURIN and multiple other proteins as potential novel drug targets for treatment of IHD. (J Am Coll Cardiol 2023;82:1906-1920)(c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

SummaryChina Kadoorie Biobank is a population-based prospective cohort of >512,000 adults recruited in 2004-2008 from 10 geographically diverse regions across China. Detailed data from questionnaire and physical measurements were collected at baseline, with additional measurements at three resurveys involving approximately 5% of surviving participants. Incident disease events are captured through electronic linkage to death and disease registries and to the national health insurance system. Genome-wide genotyping has been conducted for >100,000 participants using custom-designed Axiom® arrays. Analysis of these data reveals extensive relatedness within the CKB cohort, signatures of recent consanguinity, and principal component signatures reflecting large-scale population movements from recent Chinese history. In addition to numerous CKB studies of candidate drug targets and disease risk factors, CKB has made substantial contributions to many international genetics consortia. Collected biosamples are now being used for high-throughput ‘omics assays which, together with planned whole genome sequencing, will continue to enhance the scientific value of this biobank.

Background: Mendelian randomization studies of systolic blood pressure (SBP) can assess the shape and strength of the associations of genetically predicted differences in SBP with major disease outcomes and are less constrained by biases in observational analyses. This study aimed to compare the associations of usual and genetically predicted SBP with major cardiovascular disease (CVD) outcomes, overall and by levels of SBP, age, and sex. Methods: The China Kadoorie Biobank involved a 12-year follow-up of a prospective study of 489 495 adults aged 40 to 79 years with no prior CVD and 86 060 with genetic data. Outcomes included major vascular events (59 490/23 151 in observational/genetic analyses), and its components (ischemic stroke [n=39 513/12 043], intracerebral hemorrhage [7336/5243], and major coronary events [7871/4187]). Genetically predicted SBP used 460 variants obtained from European ancestry genome-wide studies. Cox regression estimated adjusted hazard ratios for incident CVD outcomes down to usual SBP levels of 120 mm Hg. Results: Both observational and genetic analyses demonstrated log-linear positive associations of SBP with major vascular event and other major CVD types in the range of 120 to 170 mm Hg. Consistent with the observational analyses, the hazard ratios per 10 mm Hg higher genetically predicted SBP were 2-fold greater for intracerebral hemorrhage (1.71 [95% CI, 1.58–1.87]) than for ischemic stroke (1.37 [1.30–1.45]) or major coronary event (1.29 [1.18–1.42]). Genetic analyses also demonstrated 2-fold greater hazard ratios for major vascular event in younger (1.69 [95% CI, 1.54–1.86]) than in older people (1.28 [1.18–1.38]). Conclusions: The findings provide support for initiation of blood pressure-lowering treatment at younger ages and below the conventional cut-offs for hypertension to maximize CVD prevention, albeit the absolute risks of CVD are far greater in older people.