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OBJECTIVE: Integrated analyses of plasma proteomics and genetic data in prospective studies can help assess the causal relevance of proteins, improve risk prediction, and discover novel protein drug targets for type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We measured plasma levels of 2,923 proteins using Olink Explore among ∼2,000 randomly selected participants from China Kadoorie Biobank (CKB) without prior diabetes at baseline. Cox regression assessed associations of individual protein with incident T2D (n = 92 cases). Proteomic-based risk models were developed with discrimination, calibration, reclassification assessed using area under the curve (AUC), calibration plots, and net reclassification index (NRI), respectively. Two-sample Mendelian randomization (MR) analyses using cis -protein quantitative trait loci identified in a genome-wide association study of CKB and UK Biobank for specific proteins were conducted to assess their causal relevance for T2D, along with colocalization analyses to examine shared causal variants between proteins and T2D. RESULTS: Overall, 33 proteins were significantly associated (false discovery rate <0.05) with risk of incident T2D, including IGFBP1, GHR, and amylase. The addition of these 33 proteins to a conventional risk prediction model improved AUC from 0.77 (0.73–0.82) to 0.88 (0.85–0.91) and NRI by 38%, with predicted risks well calibrated with observed risks. MR analyses provided support for the causal relevance for T2D of ENTR1, LPL, and PON3, with replication of ENTR1 and LPL in Europeans using different genetic instruments. Moreover, colocalization analyses showed strong evidence (pH4 > 0.6) of shared genetic variants of LPL and PON3 with T2D. CONCLUSIONS: Proteomic analyses in Chinese adults identified novel associations of multiple proteins with T2D with strong genetic evidence supporting their causal relevance and potential as novel drug targets for prevention and treatment of T2D. [ABSTRACT FROM AUTHOR]

Background and Aims: Sex‐specific associations of sex hormone‐binding globulin (SHBG) and bioavailable testosterone (BAT) with NAFLD remain indeterminate. We aimed to explore observational and genetically determined relationships between each hormone and NAFLD. Methods: We included 187 395 men and 170 193 women from the UK Biobank. Linear and nonlinear Cox regression models and Mendelian randomization (MR) analysis were used to test the associations. Results: During 12.49 years of follow‐up, 2209 male and 1886 female NAFLD cases were documented. Elevated SHBG levels were linearly associated with a lower risk of NAFLD in women (HR (95% CI),.71 (.63,.79)), but not in men (a "U" shape, pnon‐linear <.001). Higher BAT levels were associated with a lower NAFLD risk in men (HR (95% CI),.81 (.71,.93)) but a higher risk in women (HR (95% CI): 1.25 (1.15, 1.36)). Genetically determined SHBG and BAT levels were linearly associated with NAFLD risk in women (OR (95% CI):.57 (.38,.87) and 2.21 (1.41, 3.26) respectively); in men, an "L‐shaped" MR association between SHBG levels and NAFLD risk was found (pnon‐linear =.016). The bidirectional MR analysis further revealed the effect of NAFLD on SHBG and BAT levels in both sexes. Conclusions: Consistently, linear associations of lower SHBG and higher BAT levels with increased NAFLD risk were both conventionally and genetically found in women, while in men, SHBG acts in a nonlinear manner. In addition, NAFLD may affect SHBG and BAT levels. [ABSTRACT FROM AUTHOR]

Background The role of genetic background underlying the disparity of relative risk of smoking and lung cancer between European populations and East Asians remains unclear. Methods To assess the role of ethnic differences in genetic factors associated with smoking-related risk of lung cancer, we first constructed ethnic-specific polygenic risk scores (PRSs) to quantify individual genetic risk of lung cancer in Chinese and European populations. Then, we compared genetic risk and smoking as well as their interactions on lung cancer between two cohorts, including the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). We also evaluated the absolute risk reduction over a 5-year period. Results Differences in compositions and association effects were observed between the Chinese-specific PRSs and European-specific PRSs, especially for smoking-related loci. The PRSs were consistently associated with lung cancer risk, but stronger associations were observed in smokers of the UKB [hazard ratio (HR) 1.26 vs 1.15, P  =   0.028]. A significant interaction between genetic risk and smoking on lung cancer was observed in the UKB (RERI, 11.39 (95% CI, 7.01–17.94)], but not in the CKB. Obvious higher absolute risk was observed in nonsmokers of the CKB, and a greater absolute risk reduction was found in the UKB (10.95 vs 7.12 per 1000 person-years, P  <0.001) by comparing heavy smokers with nonsmokers, especially for those at high genetic risk. Conclusions Ethnic differences in genetic factors and the high incidence of lung cancer in nonsmokers of East Asian ethnicity were involved in the disparity of smoking-related risk of lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: Different populations may exhibit differences in dietary intakes, which may result in heterogeneities in diet–disease associations. We compared intakes of major food groups overall, by sex, and by socio-economic status (SES) (defined as both education and income), between participants in the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). Methods: Data were from ~ 25,000 CKB participants who completed a validated interviewer-administered computer-based questionnaire (2013–2014) and ~ 74,000 UKB participants who completed ≥ 3 web-based 24-h dietary assessments (2009–2012). Intakes of 12 major food groups and five beverages were harmonized and compared between the cohorts overall, by sex and by SES. Multivariable-adjusted linear regression examined the associations between dietary intakes and body mass index (BMI) in each cohort. Results: CKB participants reported consuming more rice, eggs, vegetables, soya products, and less wheat, other staple foods (other than rice and wheat), fish, poultry, all dairy products, fruit, and beverages compared to UKB participants. Red meat intake was similar in both cohorts. Having a higher SES was generally associated with a higher consumption of foods and beverages in CKB, whereas in UKB dietary intakes differed more by education and income, with a positive association observed for meat and income in both UKB and CKB but an inverse association observed for education in UKB. Associations of dietary intakes with BMI varied between the two cohorts. Conclusion: The large differences in dietary intakes and their associations with SES and BMI could provide insight into the interpretation of potentially different diet–disease associations between CKB and UKB. [ABSTRACT FROM AUTHOR]

Background: Both genetic and cardiovascular factors contribute to the risk of developing heart failure (HF), but whether idea cardiovascular health metrics (ICVHMs) offset the genetic association with incident HF remains unclear.Objectives: To investigate the genetic association with incident HF as well as the modification effect of ICVHMs on such genetic association in Chinese and British populations.Methods: An ICVHMs based on smoking, drinking, physical activity, diets, body mass index, waist circumference, blood pressure, blood glucose, and blood lipids, and a polygenic risk score (PRS) for HF were constructed in the China Kadoorie Biobank (CKB) of 96,014 participants and UK Biobank (UKB) of 335,782 participants which were free from HF and severe chronic diseases at baseline.Results: During the median follow-up of 11.38 and 8.73 years, 1451 and 3169 incident HF events were documented in CKB and UKB, respectively. HF risk increased monotonically with the increase of PRS per standard deviation (CKB: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07, 1.32; UKB: 1.07; 1.03, 1.11; P for trend < 0.001). Each point increase in ICVHMs was associated with 15% and 20% lower risk of incident HF in CKB (0.85; 0.81, 0.90) and UKB (0.80; 0.77, 0.82), respectively. Compared with unfavorable ICVHMs, favorable ICVHMs was associated with a lower HF risk, with 0.71 (0.44, 1.15), 0.41 (0.22, 0.77), and 0.48 (0.30, 0.77) in the low, intermediate, and high genetic risk in CKB and 0.34 (0.26, 0.44), 0.32 (0.25, 0.41), and 0.37 (0.28, 0.47) in UKB (P for multiplicative interaction > 0.05). Participants with low genetic risk and favorable ICVHMs, as compared with high genetic risk and unfavorable ICVHMs, had 56~72% lower risk of HF (CKB 0.44; 0.28, 0.70; UKB 0.28; 0.22, 0.37). No additive interaction between PRS and ICVHMs was observed (relative excess risk due to interaction was 0.05 [-0.22, 0.33] in CKB and 0.04 [-0.14, 0.22] in UKB).Conclusions: In CKB and UKB, genetic risk and ICVHMs were independently associated with the risk of incident HF, which suggested that adherence to favorable cardiovascular health status was associated with a lower HF risk among participants with all gradients of genetic risk. [ABSTRACT FROM AUTHOR]

Background Resting heart rate (RHR) has been associated with risks of mortality and multiple chronic diseases. Previous studies, predominantly conducted in Europeans, have reported 91 independent variants associated with RHR and its genetic correlations with several cardiometabolic traits. Studies from East Asians are lacking. Methods We performed a GWAS for RHR in 87,701 participants aged 30-79 years from China Kadoorie Biobank (CKB). A linear mixed model was used under an additive model. Replication was conducted in 37,251 Chinese participants from CKB and UK Biobank. We conducted LD score regression to quantify genetic correlations across RHR and 11 cardiometabolic traits. Results Only 50 previously reported variants were replicated in CKB (=0.025). We identified ten novel loci associated with RHR (P <5 × 10-8), of which 50 candidate genes were prioritized. RHR showed significant genetic correlations with diastolic blood pressure (rg=0.258, P =5.71 × 10−10), mean arterial pressure (rg=0.225, P =3.08 × 10−8), systolic blood pressure (rg=0.170, P =4.92 × 10−5), plasma glucose (rg=0.197, P =0.003), total cholesterol (rg=0.287, P =0.012), and high-density lipoprotein (rg=0.246, P =0.030). Conclusions We identified ten novel loci associated with RHR in a large Asian cohort. The identified genetic correlations of RHR with blood pressure, glucose, and lipids indicate previously reported association of RHR with risk of all-cause death might be mediated via its correlations with cardiometabolic traits. Key messages Ten novel loci associated with RHR were identified in the Chinese population. RHR showed significant genetic correlations with blood pressure, glucose and lipids. [ABSTRACT FROM AUTHOR]

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. The purpose of this study was to examine associations of proteomics and genetics data with IHD in population studies to discover novel preventive treatments. 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). 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 CARDIOGRAM+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, Asialoglycoprotein 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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Little is known about the population-based mismatch between phenotypic and genetic BMI (BMI-PGM) and its association with type 2 diabetes. We therefore used data from the China Kadoorie Biobank and UK Biobank and calculated BMI-PGM for each participant as the difference between the percentile for adjusted BMI at baseline and the percentile for adjusted polygenic risk score for BMI. Participants were categorized into discordantly low (BMI-PGM < the first quartile), concordant (the first quartile ≤ BMI-PGM < the third quartile), and discordantly high (BMI-PGM ≥ the third quartile) groups. We calculated adjusted hazard ratios (HRs) for the association of BMI-PGM and type 2 diabetes using Cox proportional hazard models in each cohort, and combined HRs using random-effects meta-analyses. During a median follow-up of 12 years for both cohorts, BMI-PGM was associated with the risk of type 2 diabetes, with the discordantly low group showing reduced risk and the discordantly high group showing elevated risk compared with the concordant group, independent of BMI and other conventional risk factors. In addition, normal-weight individuals with discordantly high BMI-PGM faced a higher risk of type 2 diabetes than overweight individuals. These findings suggest that BMI-PGM may play a potential role in reassessing the risk of type 2 diabetes, particularly among normal-weight populations., Article Highlights: Social developments have fostered an "obesogenic environment" that exacerbated phenotypic versus genetic mismatch of BMI (BMI-PGM) and the risk of type 2 diabetes. The study quantified BMI-PGM and examined its association with type 2 diabetes independent of BMI and other conventional factors. The risk of type 2 diabetes was lower in the discordantly low BMI-PGM group and higher in the discordantly high BMI-PGM group, with concordant BMI-PGM group as reference. These findings indicate the potential to reassess type 2 diabetes risk by quantifying BMI-PGM on individual levels., (© 2024 by the American Diabetes Association.)

Background: Observational studies have shown a controversial relationship between dietary fat intake and Alzheimer's disease, and the causal effects are unclear., Aims: To assess the causal effects of total fat, saturated fat and polyunsaturated fat (PUF) intakes on the risk of Alzheimer's disease., Method: A two-sample Mendelian randomisation analysis was performed using genome-wide association study summary statistics on different types of fat intake from UK Biobank ( n = 51 413) and on late-onset Alzheimer's disease (LOAD; 4282 cases, n = 307 112) and all forms of Alzheimer's disease (6281 cases, n = 309 154) from the FinnGen consortium. In addition, a multivariable Mendelian randomisation (MVMR) analysis was conducted to estimate the effects independent of carbohydrate and protein intakes., Results: Genetically predicted per standard deviation increase in the total fat and saturated fat intakes were associated with 44 and 38% higher risks of LOAD (total fat: odds ratio = 1.44, 95% CI 1.03-2.02; saturated fat: odds ratio = 1.38, 95% CI 1.002-1.90; P = 0.049). The associations remained significant in the MVMR analysis (total fat: odds ratio = 3.31, 95% CI 1.74-6.29; saturated fat: odds ratio = 2.04, 95% CI 1.16-3.59). Total fat and saturated fat intakes were associated with a higher risk of all forms of Alzheimer's disease in the MVMR analysis (total fat: odds ratio = 2.09, 95% CI 1.22-3.57; saturated fat: odds ratio = 1.60, 95% CI 1.01-2.52). The PUF intake was not associated with LOAD or all forms of Alzheimer's disease., Conclusions: This study indicated that total dietary fat intake, especially saturated fat, contributed to the risk of Alzheimer's disease, and the effects were independent of other nutrients. These findings informed prevention strategies and management for Alzheimer's disease directly towards reducing dietary saturated fat intake.

Background: Little is known about the underlying relationship between mosaic loss of chromosome Y (mLOY), the most common chromosomal alterations in older men, and the risk of age-related lung diseases., Methods: We included 217 780 participants from the UK Biobank (UKB) and 42 859 participants from the China Kadoorie Biobank. The mLOY events were detected using the Mosaic Chromosomal Alterations (MoChA) pipeline. Outcomes included all lung diseases, COPD, lung cancer and idiopathic pulmonary fibrosis (IPF). Cox proportional hazard models were fitted to estimate the hazard ratios and 95% confidence intervals of mLOY with lung diseases in both cohorts. The combined hazard ratios were derived from meta-analysis., Results: Results from the two cohorts showed that expanded mLOY was associated with increased risks of all lung diseases (HR 1.19 (95% CI 1.04-1.36)), COPD (HR 1.20 (95% CI 1.13-1.28)), lung cancer (HR 1.34 (95% CI 1.21-1.48)) and IPF (HR 1.34 (95% CI 1.16-1.56) in the UKB). There was evidence of positive interactions between mLOY and smoking behaviour (relative excess risk due to interaction (97.5% CI) >0). Additionally, we observed that current smokers with expanded mLOY had the highest risk of incident lung diseases in both cohorts., Conclusions: mLOY may be a novel predictor for age-related lung diseases. For current smokers carrying mLOY, adopting quitting smoking behaviour may contribute to substantially reducing their risk of incident lung diseases., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations., (© 2024. The Author(s).)

Aims: Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses of PCSK9 genetic variants in large biobanks can help to identify unexpected effects of PCSK9 inhibition., Methods and Results: In the prospective China Kadoorie Biobank, we constructed a genetic score using three variants at the PCSK9 locus associated with directly measured LDL-C [PCSK9 genetic score (PCSK9-GS)]. Logistic regression gave estimated odds ratios (ORs) for PCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1 SD lower LDL-C. PCSK9-GS was associated with lower risks of carotid plaque [n = 8340 cases; OR = 0.61 (95% confidence interval: 0.45-0.83); P = 0.0015], major occlusive vascular events [n = 15 752; 0.80 (0.67-0.95); P = 0.011], and ischaemic stroke [n = 11 467; 0.80 (0.66-0.98); P = 0.029]. However, PCSK9-GS was also associated with higher risk of hospitalization with chronic obstructive pulmonary disease [COPD: n = 6836; 1.38 (1.08-1.76); P = 0.0089] and with even higher risk of fatal exacerbations amongst individuals with pre-existing COPD [n = 730; 3.61 (1.71-7.60); P = 7.3 × 10-4]. We also replicated associations for a PCSK9 variant, reported in UK Biobank, with increased risks of acute upper respiratory tract infection (URTI) [pooled OR after meta-analysis of 1.87 (1.38-2.54); P = 5.4 × 10-5] and self-reported asthma [pooled OR of 1.17 (1.04-1.30); P = 0.0071]. There was no association of a polygenic LDL-C score with COPD hospitalization, COPD exacerbation, or URTI., Conclusion: The LDL-C-lowering PCSK9 genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease but higher risks of respiratory diseases. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections., Lay Summary: Genetic analyses of over 100 000 participants of the China Kadoorie Biobank, mimicking the effect of new drugs intended to reduce cholesterol by targeting the PCSK9 protein, have identified potential severe effects of lower PCSK9 activity in patients with existing respiratory disease.PCSK9 genetic variants that are associated with lower cholesterol and reduced rates of cardiovascular disease are also associated with increased risk of a range of respiratory diseases, including asthma, upper respiratory tract infections, and hospitalization with chronic obstructive pulmonary disease (COPD).These genetic variants are not associated with whether or not individuals have COPD; instead, they are specifically associated with an increase in the chance of those who already have COPD being hospitalized and even dying, suggesting that careful monitoring of such patients should be considered during development of and treatment with anti-PCSK9 medication., Competing Interests: Conflict of interest: The Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford (CTSU) is co-ordinating a PCSK9 phase III cardiovascular outcome trial (ORION 4). M.V.H. has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of CTSU did not accept any personal payment. M.V.H. was at the University of Oxford when this work was conducted and is presently employed by 23andMe and holds stock in 23andMe., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To quantify the association of combined sleep behaviours and genetic susceptibility with the incidence of cardiovascular disease (CVD)., Methods and Results: This study included 385 292 participants initially free of CVD from UK Biobank. We newly created a healthy sleep score according to five sleep factors and defined the low-risk groups as follows: early chronotype, sleep 7-8 h per day, never/rarely insomnia, no snoring, and no frequent excessive daytime sleepiness. Weighted genetic risk scores of coronary heart disease (CHD) or stroke were calculated. During a median of 8.5 years of follow-up, we documented 7280 incident CVD cases including 4667 CHD and 2650 stroke cases. Compared to those with a sleep score of 0-1, participants with a score of 5 had a 35% (19-48%), 34% (22-44%), and 34% (25-42%) reduced risk of CVD, CHD, and stroke, respectively. Nearly 10% of cardiovascular events in this cohort could be attributed to poor sleep pattern. Participants with poor sleep pattern and high genetic risk showed the highest risk of CHD and stroke., Conclusion: In this large prospective study, a healthy sleep pattern was associated with reduced risks of CVD, CHD, and stroke among participants with low, intermediate, or high genetic risk., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)