UK Biobank Study Research Articles

Associations of Metabolic Dysfunction-Associated Fatty Liver Disease With Peripheral Artery Disease: Prospective Analysis in the UK Biobank and ARIC Study.

There is currently limited evidence comparing the association between metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic fatty liver disease (NAFLD), and the risk of peripheral artery disease (PAD). This study aims to analyze the associations of MAFLD and NAFLD with incident PAD. Two longitudinal studies, the UKB (UK Biobank) study (n=372 216) and the ARIC (Atherosclerosis Risk in Communities) study (n=4681), categorized participants into MAFLD/non-MAFLD groups and NAFLD/non-NAFLD groups. Subsequently, participants were classified into 4 groups: non-fatty liver disease, MAFLD-only, NAFLD-only, and both MAFLD and NAFLD groups. Cox proportional hazard model estimated associations of MAFLD/NAFLD status, subtypes, and liver fibrosis severity with PAD risk. The MAFLD group had a higher risk of incident PAD compared with the non-MAFLD group, and similarly, the NAFLD group had a higher risk compared with the non-NAFLD group. Among these 4 groups, the MAFLD-only group had the strongest association with the risk of incident PAD, while the NAFLD-only group was not independently associated. Diabetic MAFLD subtype was significantly associated with increased PAD risk, and higher level of liver fibrosis scores correlated with elevated PAD risk. Both MAFLD and NAFLD are significantly associated with an increased incidence of PAD, with stronger associations in MAFLD and diabetic MAFLD population. These findings emphasize that the need for screening and prevention strategies for PAD in this high-risk population is warranted. The assessment of MAFLD and its subtypes should be considered as an integral component of cardiovascular risk assessment.

Impact of Metabolic Syndrome Traits on Kidney Disease Risk in Individuals with MASLD: A UK Biobank Study.

The impact of metabolic syndrome (MetS) traits on chronic kidney disease (CKD) risk in metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. We investigated the impact of type and number of MetS traits and liver fibrosis on prevalent CKD and incident end-stage renal disease (ESRD) risk in SLD. 234 488 UK Biobank participants' were analysed. Hepatic steatosis index (> 36 for SLD, < 30 for no SLD) and MRI-proton density fat fraction (≥ 5.56%) were used to identify SLD. MetS traits were identified using MASLD criteria. Advanced fibrosis (FIB-4 score > 2.67) was determined using FIB-4 scores. eGFR < 60 mL/min/1.73 m2 or albuminuria > 3 mg/mmol identified prevalent CKD. A validated algorithm identified incident ESRD. Binary logistic and Cox regressions were used to test associations with prevalent CKD ([adjusted odds ratios (ORs)]) and incident ESRD (adjusted hazard ratios [HRs]) respectively. 102 410 participants (41.2%) had SLD. 64.4% had MetS. 1.3% had FIB-4 score > 2.67. With SLD and only one MetS trait, hypertension (OR 1.35, 95% CI 1.35-1.72) or type 2 diabetes (T2D) (OR 1.89, 95% CI 1.06-3.38) increased risk of prevalent CKD. MetS (≥ 3 traits) increased prevalent CKD risk (OR 1.94, 95% CI 1.75-2.15), which was further increased by advanced liver fibrosis (OR 4.29, 95% CI 3.36-5.47). CKD prevalence increased with increasing MetS traits. Over 13.6 years (median follow-up), MetS was associated with increased risk of developing ESRD (HR 1.70, 95% CI 1.19-2.43). In MASLD, hypertension, and T2D, number of MetS traits and liver fibrosis increased risk of prevalent CKD and presence of MetS increased the risk of incident ESRD.

Accounting for bias due to outcome data missing not at random: comparison and illustration of two approaches to probabilistic bias analysis: a simulation study.

Bias from data missing not at random (MNAR) is a persistent concern in health-related research. A bias analysis quantitatively assesses how conclusions change under different assumptions about missingness using bias parameters that govern the magnitude and direction of the bias. Probabilistic bias analysis specifies a prior distribution for these parameters, explicitly incorporating available information and uncertainty about their true values. A Bayesian bias analysis combines the prior distribution with the data's likelihood function whilst a Monte Carlo bias analysis samples the bias parameters directly from the prior distribution. No study has compared a Monte Carlo bias analysis to a Bayesian bias analysis in the context of MNAR missingness. We illustrate an accessible probabilistic bias analysis using the Monte Carlo bias analysis approach and a well-known imputation method. We designed a simulation study based on a motivating example from the UK Biobank study, where a large proportion of the outcome was missing and missingness was suspected to be MNAR. We compared the performance of our Monte Carlo bias analysis to a principled Bayesian bias analysis, complete case analysis (CCA) and multiple imputation (MI) assuming missing at random. As expected, given the simulation study design, CCA and MI estimates were substantially biased, with 95% confidence interval coverages of 7-48%. Including auxiliary variables (i.e., variables not included in the substantive analysis that are predictive of missingness and the missing data) in MI's imputation model amplified the bias due to assuming missing at random. With reasonably accurate and precise information about the bias parameter, the Monte Carlo bias analysis performed as well as the Bayesian bias analysis. However, when very limited information was provided about the bias parameter, only the Bayesian bias analysis was able to eliminate most of the bias due to MNAR whilst the Monte Carlo bias analysis performed no better than the CCA and MI. The Monte Carlo bias analysis we describe is easy to implement in standard software and, in the setting we explored, is a viable alternative to a Bayesian bias analysis. We caution careful consideration of choice of auxiliary variables when applying imputation where data may be MNAR.

Bidirectional Risk Modulator and Modifier Variant of Dilated and Hypertrophic Cardiomyopathy in BAG3.

The genetic factors that modulate the reduced penetrance and variable expressivity of heritable dilated cardiomyopathy (DCM) are largely unknown. BAG3 genetic variants have been implicated in both DCM and hypertrophic cardiomyopathy (HCM), nominating BAG3 as a gene that harbors potential modifier variants in DCM. To interrogate the clinical traits and diseases associated with BAG3 coding variation. This was a cross-sectional study in the Penn Medicine BioBank (PMBB) enrolling patients of the University of Pennsylvania Health System's clinical practice sites from 2014 to 2023. Whole-exome sequencing (WES) was linked to electronic health record (EHR) data to associate BAG3 coding variants with EHR phenotypes. This was a health care population-based study including individuals of European and African genetic ancestry in the PMBB with WES linked to EHR phenotypes, with replication studies in BioVU, UK Biobank, MyCode, and DCM Precision Medicine Study. Carrier status for BAG3 coding variants. Association of BAG3 coding variation with clinical diagnoses, echocardiographic traits, and longitudinal outcomes. In PMBB (n = 43 731; median [IQR] age, 65 [50-76] years; 21 907 female [50.1%]), among 30 324 European and 11 198 African individuals, the common C151R variant was associated with decreased risk for DCM (odds ratio [OR], 0.85; 95% CI, 0.78-0.92) and simultaneous increased risk for HCM (OR, 1.59; 95% CI, 1.25-2.02), which was confirmed in the replication cohorts. C151R carriers exhibited improved longitudinal outcomes compared with noncarriers as assessed by age at death (hazard ratio [HR], 0.85; 95% CI, 0.74-0.96; median [IQR] age, 71.8 [63.1-80.7] in carriers and 70.3 [61.6-79.2] in noncarriers) and heart transplant (HR, 0.81; 95% CI, 0.66-0.99; median [IQR] age, 56.7 [46.1-63.1] in carriers and 55.6 [45.2-62.9] in noncarriers). C151R was associated with reduced risk of DCM (OR, 0.42; 95% CI, 0.24-0.74) and heart failure (OR, 0.27; 95% CI, 0.14-0.50) among individuals harboring truncating TTN variants in exons with high cardiac expression (n = 358). BAG3 C151R was identified as a bidirectional modulator of risk along the DCM-HCM spectrum, as well as an important genetic modifier variant in TTN-mediated DCM. This work expands on the understanding of the etiology and penetrance of DCM, suggesting that BAG3 C151R is an important genetic modifier variant contributing to the variable expressivity of DCM, warranting further exploration of its mechanisms and of genetic modifiers in DCM more broadly.

Abstract 4121589: Sex differences in Social Determinants of Health and Adverse Outcomes in Atrial Fibrillation: A UK Biobank Study

Background: Beyond the risk of thromboembolic stroke, people with atrial fibrillation (AF) are substantially burdened with a higher incidence of cardiovascular mortality, even among patients treated with anticoagulants. The reasons behind these outcomes are only partially understood. Social determinants of health (SDOH), strong independent predictors of major adverse cardiovascular events (MACE) in several cardiac diseases, may play a role; however, their impact on AF prognosis and the differences in SDOH by sex have been insufficiently explored. Objective: We investigated the sex differences in the association between SDOH and MACE in patients with AF. Methods: Data from the UK Biobank included participants enrolled from 2006 to 2010. An incident AF patient cohort, free of stroke and MI was created. Seventeen SDOH derived from three domains:: socio-economic status, psychosocial factors, and neighborhood/living environment were identified Cox proportional hazards models were used to evaluate the associations of individual SDOH components with the risk of MACE stratified by sex. Covariates including all variables of the CHA 2 DS 2 -VASc Score (Congestive heart failure, Hypertension, Age, Diabetes, prior stroke or transient ischemic attack, Vascular disease and Sex), current use of antiplatelet therapy or anticoagulation, smoking and body mass index. The primary outcome was a composite of MACE (including stroke, transient ischemic attack and arterial thromboembolic event, MI and cardiovascular mortality) and all-cause mortality. Results: A total of 23,113 participants with AF (mean age, 62.44 ± 5.88 years; female sex 39.7%) were included. The composite outcome occurred in 5,151 (22%) of participants over 10-year follow up. In the multivariate adjusted model, several SDOH were independently associated with an increased risk of adverse outcomes. Males showed a broader range of SDOH that were significantly associated with outcomes, including unfavourable economic factors and low social support. Despite females had fewer significant SDOH, education-related factors and local crime rates were significant predictors of adverse outcomes (Figure 1). Conclusions: Adverse SDOHs are associated with a higher risk of MACE and all-cause mortality in AF, with sex-specific variations. These findings underscore the need of incorporating routinely SDOH assessment into clinical practice to more accurately stratify risk and tailor preventive strategies based on sex-specific data.

Abstract 4136040: Wearable Device-Measured Physical Activity and Incident Cardiovascular Diseases In Cancer Survivors

Background: Cardiovascular diseases (CVD) is the leading cause of non-cancer mortality among cancer survivors. Despite the known benefits of physical activity on cardiovascular health in the general population, evidence regarding post-diagnosis physical activity and CVD risk among cancer survivors is limited. Objectives: To explore the associations of wearable device-measured moderate-to-vigorous intensity physical activity (MVPA) with CVD risk in long-term cancer survivors. Methods: The retrospective analysis involved a prospective cohort of 6109 cancer survivors without CVD from the UK Biobank accelerometry subsample. Cancer diagnoses were obtained from national cancer registries (International Classification of Diseases-10 [ICD-10], C00-C97, except for non-melanoma skin cancer, in situ, and non-well-defined cancers), and participants were followed up through December 31, 2022. A machine-learning algorithm was utilized to categorize MVPA into four groups based on guideline-recommend MVPA duration (0-75 min/week, 75-150 min/week, 150-300 min/week, ≥300 min/week). Results: Over a median follow-up of 7.88 years, there were 539 incident CVD events, including 361 incident CAD events, 155 incident HF events, and 109 incident stroke events. A clear inverse linear dose-response relationship between MVPA volume and the incidence of CVD was observed (P for nonlinear=0.49), with no maximal threshold for the benefits. Adjusted CVD incidence rates (95% confidence intervals [CIs]) across MVPA groups (0-75 min/week, 75-150 min/week, 150-300 min/week, ≥300 min/week) were 15.30 (12.90, 18.10), 13.50 (11.00, 16.40), 12.00 (10.20, 14.10), and 9.86 (8.35, 11.60) per 1000 person-years, respectively. Adjusted hazard ratios (95% CI) for CVD, CAD, HF, and stroke in the highest MVPA group (≥300 min/week) compared with those with the lowest MVPA group (0-75 min/week) were 0.63 (0.49, 0.80), 0.68 (0.51, 0.91), 0.66 (0.42,1.06), 0.72 (0.42, 1.23), respectively. Conclusions: Findings from the UK Biobank study suggest that longer durations of MVPA are associated with reduced incident CVD risk in cancer survivors, particularly in CAD risk reduction, underscoring the potential for physical activity to serve as a key component in cardio-oncology care.

Abstract 4113263: Serum Metabolomics Adds Predictive Value to Clinical and Polygenic Risk Scores for Atrial Fibrillation: A UK Biobank study of &gt;240,000 Patients

Background: Atrial fibrillation (AF) poses substantial morbidity and mortality burdens globally. It is critical to identify individuals at high-risk for AF to implement both lifestyle modifications and close monitoring for initiation of oral anticoagulants. Currently, risk prediction in AF relies on clinical scores such as CHARGE-AF. Small molecule metabolites are thought to play a role in AF pathogenesis, but the additional predictive value of metabolomics over clinical and genetic risk factors is unknown. Using the UK Biobank (UKBB), we sought to perform this evaluation. Methods: We included all UKBB participants with complete 1 H-NMR metabolite measurements. We excluded participants with prior history of AF or with incomplete AF Polygenic Risk Score (AF-PRS) or CHARGE-AF components. The final cohort included 240,628 patients. In-patient records, primary care notes, and death registries were queried to identify patients who had developed incident AF within 5 years of enrollment. The cohort was divided into a 80/20:Train/Test split. We compared the performance of an Elastic-Net regularized Cox Proportional Hazards (EN-CPH) model trained on CHARGE-AF, AF-PRS, and the full 170 metabolite panel to a CPH model trained only on CHARGE-AF and AF-PRS. Results: Within 5 years, 4,174 (1.7%) patients developed AF. Compared to the control population, the incident AF cases were more likely to be older (62 vs. 56, p&lt;0.001), male (65% vs 45%, p&lt;0.001), and have higher CHARGE-AF and AF-PRS scores (p&lt;0.001). After training the EN-CPH model on CHARGE-AF, AF-PRS, and 170 metabolites, the final model included 8 metabolites on top of CHARGE-AF (HR: 1.28) and AF-PRS (HR: 1.11). After adjusting for CHARGE-AF and AF-PRS, creatinine level was associated with increased risk of AF (HR: 1.01) while linoleic acid level (HR: 0.985) was associated with decreased risk. Furthermore, total cholesterol, esterified cholesterol, free cholesterol, cholesteryl esters in IDL, omega-6 fatty acids, and cholesterol in large LDL were associated with HR 0.993-0.999. The EN-CPH model out-performed the CPH model without metabolomics on the test set (AUC 0.786 vs 0.753, p &lt; 0.001). Conclusions: The addition of metabolomics to clinical and genomic risk scores improves prediction of 5-year incident AF within a general population. This study highlights the significance of the metabolome as an independent prognosticator of AF risk. Further study of the mechanisms by which selected metabolites alter AF risk is needed.

Gastroesophageal reflux disease and risk of incident lung cancer: A large prospective cohort study in UK Biobank.

Some pathogenic mechanisms suggest a potential relationship between gastroesophageal reflux disease (GERD) and respiratory diseases. However, evidence regarding the association between GERD and lung cancer is mixed. We aim to explore this relationship based on data from the large-scale UK Biobank study. We performed a cross-sectional and prospective cohort study in 501,569 (45.58% male) individuals included in the UK Biobank at baseline (2006-2010). The Cox proportional hazards model and logistic regression models were used to assess the relationship between GERD and lung cancer, small cell lung cancer (SCLC), lung squamous cell carcinoma (LUSC), and lung adenocarcinoma (LUAD). During a mean follow-up of 11.54 years, 3,863 (0.84%) incident lung cancer cases were identified. In the cross-sectional analysis using logistic models, significant associations were found between GERD and prevalent lung cancer cases (odds ratio [OR] = 1.87, 95% confidence interval [95% CI]: 1.45-2.38) and subtypes of lung cancer, with an OR (95% CI) of 3.19 (1.47-6.79) for SCLC, 2.08 (1.33-3.21) for LUSC, 1.85 (1.15-2.91) for LUAD. In the follow-up analysis using Cox models, GERD was associated with an increased risk of lung cancer (hazard ratio [HR] = 1.24, 95%CI: 1.14-1.34). Similar associations were also observed between GERD and SCLC (HR = 1.39, 95% CI: 1.09-1.78), LUSC (HR = 1.40, 95% CI: 1.18-1.65), and LUAD (HR = 1.17, 95% CI: 1.02-1.33). The risk of lung cancer resulting from GERD was mainly elevated in former smokers (HR = 1.38, 95% CI: 1.23-1.54) and current smokers (HR = 1.18, 95% CI: 1.04-1.34), but not in never-smokers (HR = 0.89, 95% CI: 0.70-1.14). No significant association was observed in former smokers who had quit smoking for at least 25 years. We found that GERD was positively associated with an increased risk of lung cancer, especially among smokers. Awareness of this association may be beneficial for prevention and treatment strategies of both diseases.

Observational and genetic associations between cardiorespiratory fitness and age-related diseases: longitudinal analyses in the UK Biobank study

Observational and genetic associations between cardiorespiratory fitness and age-related diseases: longitudinal analyses in the UK Biobank study

Exploring potential therapeutic targets for asthma: a proteome-wide Mendelian randomization analysis

BackgroundAsthma poses a significant global health challenge, characterized by high rates of morbidity and mortality. Despite available treatments, many severe asthma patients remain poorly managed, highlighting the need for novel therapeutic strategies. This study aims to identify potential drug targets for asthma by examining the influence of circulating plasma proteins on asthma risk.MethodsThis study employs summary-data-based Mendelian randomization (MR) and two-sample MR methods to investigate the association between 2940 plasma proteins from the UK Biobank study and asthma. The analysis includes discovery (FinnGen cohort) and replication (GERA cohort) phases, with Bayesian colocalization used to validate the relationships between proteins and asthma. Furthermore, protein–protein interaction and druggability assessments were conducted on high-evidence strength protein biomarkers, and candidate drug prediction and molecular docking were performed for proteins without targeted drugs. Given the complexity of asthma pathogenesis, the study also explores the relationships between plasma proteins and asthma-related endpoints (e.g., obesity-related asthma, infection-related asthma, childhood asthma) to identify potential therapeutic targets for different subtypes.ResultsIn the discovery cohort, 75 plasma proteins were associated with asthma, including IL1RAP, IL1RL1, IL6, CXCL5, and CXCL8. Additionally, 6 proteins (IL4R, LTB, CASP8, MAX, PCDH12, and SCLY) were validated through co-localization analysis and validation cohort. The assessment of drug targetability revealed potential drug targets for IL4R, CASP8, and SCLY, while candidate drugs were predicted for LTB and MAX proteins. MAX exhibited strong binding affinity with multiple small molecules indicating a highly stable interaction and significant druggability potential. Analysis of the 75 proteins with 9 asthma-related endpoints highlighted promising targets such as DOK2, ITGAM, CA1, BTN2A1, and GZMB.ConclusionThese findings elucidate the link between asthma, its related endpoints, and plasma proteins, advancing our understanding of molecular pathogenesis and treatment strategies. The discovery of potential therapeutic targets offers new insights into asthma drug target research.

The genetic architecture of exercise-induced ventricular ectopy

Abstract Background Previously, we have shown that the frequency of exercise-induced premature ventricular contractions (PVCs) during and after exercise are associated with increased risk of major adverse cardiovascular events in asymptomatic individuals from the UK Biobank study1. The underlying mechanisms are, however, unclear. Several electrocardiographic markers associated with arrhythmogenesis have a known hereditary component, but the genetic underpinnings of exercise-induced ventricular ectopy have not been investigated. Purpose Our aim was to explore the genetic basis of premature ventricular ectopy during and after exercise and unveil plausible candidate genes and biological mechanisms. Methods We conducted a genome-wide association study (GWAS) for PVC frequency during exercise and recovery in &amp;gt;44,000 asymptomatic individuals of European ancestry without known cardiovascular disease from the UK Biobank study. As the distribution of PVC frequency is highly skewed (e.g. absence of negative values and excess of zero values), we first applied Gaussian transformation. Simulation studies were performed to justify that this approach would lead to valid inference. In the GWAS model, we included sex, age, UK Biobank genotyping array, and the first 10 genetic principal components as covariates. Statistical power was boosted by joint analysis of exercise and recovery PVC traits using multi-trait analysis of GWAS (MTAG)2. Genetic risk scores were constructed in independent samples from UK Biobank (N=341,948) and were tested for association with heart failure and life-threatening ventricular arrhythmias. Results We identified 4 loci for PVC frequency during exercise, and 1 locus for PVC frequency during recovery (Picture 1). Candidate genes included CRIM1, FLNC, and BAG3 for which mutations have been linked in the pathogenesis of (arrhythmogenic) cardiomyopathy. Subjects in the top 10% of the genetic risk scores had a significantly higher risk of heart failure and life-threatening ventricular arrhythmias compared to the bottom 90%, (odds ratio (OR) (95% confidence interval): 1.14 (1.08 – 1.20), p &amp;lt; 0.001; and 1.13 (1.02 – 1.24), p &amp;lt; 0.001, respectively). Conclusions Ventricular ectopic burdens during exercise and recovery have a significant heritable component. Candidate genes highlight a possible shared genetic background with inherited cardiomyopathy and a genetic risk score was associated with heart failure and ventricular arrhythmias. These findings substantial advance our understanding of the genetic basis of exercise-induced ventricular ectopy in a population-based cohort without cardiovascular disease.Miami plot of ventricular ectopic burden

Elevated risk for stroke in genetically predisposed bicuspid aortic valve disease: evidences from a mendelian randomization study

Abstract Background Patients with bicuspid aortic valve (BAV) have been recognized to have an elevated risk for stroke. However, the exact causal association between BAV and stroke remains elusive due to stroke-related comorbidities, residual confounding bias and sample size limitations of observational studies. Purpose To identify the causal relationship between genetically predisposed BAV and 15 cardiovascular diseases (CVDs), and whether calcific aortic valve stenosis (CAVS) or atrial fibrillation (AF) could serve as the mediator on the pathway from BAV to stroke by mendelian randomization (MR) approach. Methods Uncorrelated (r² &amp;lt; 0.001) and genome-wide significant (P &amp;lt; 5×10^-8) single nucleotide polymorphisms were extracted from the largest genome-wide association study statistics (2,236 patients and 11,604 controls) of BAV by Gehlen et al. Summary-level statistics for 15 CVDs were obtained from the UK Biobank study, FinnGen study, HERMES consortium, CARDIoGRAMplusC4D consortium and GIGASTROKE consortium. We used 2-sample MR to estimate the causal association between BAV and 15 CVDs, evaluated 12 potential mediators and mediated proportions within 2-step MR framework. Inverse variance weighted was utilized as primary MR analyses method. Results for each outcome from different sources were pooled using the random effect meta-analysis. False discovery rate (FDR) was calculated by Benjamini-Hochberg method to account for multiple comparisons. Results Genetically predicted per log-odds liability increase of BAV was significantly associated with aortic aneurysm (OR, 1.26; 95% CI, 1.13-1.40; FDR-adjusted P = 3.54 × 10^-4), any stroke (OR, 1.06; 95% CI, 1.02-1.09; FDR-adjusted P = 0.004), ischemic stroke (IS) (OR, 1.17; 95% CI, 1.03-1.11; FDR-adjusted P = 0.001) and cardioembolic stroke (CES) (OR, 1.15; 95% CI, 1.06-1.25; FDR-adjusted P = 0.004). No significant association were observed between BAV and another 11 CVD outcomes. Instead of CAVS, genetic liability to AF mediated the total effect of BAV on any stroke (proportion mediated = 13.2% [95% CI, 3.1% - 23.2%]), IS (proportion mediated = 10.8% [95% CI, 2.5% - 19.1%]) and CES (proportion mediated = 21.5% [95% CI, 5.3% - 37.7%]). Conclusions Genetically predisposed BAV is associated with a higher risk of any stroke, IS and CES, which could be mediated by AF. This study implies the pathophysiological processes from BAV towards stroke and highlights the clinical significance of AF intervention in reducing the incidence of stroke for BAV patients.Causal association between BAV and CVDs

Circulating metabolites associate with the QT interval in individuals without prevalent cardiovascular disease

Abstract Background Patients with metabolic syndrome have a higher prevalence of heart-rate corrected QT (QTc) interval prolongation. Despite this the effect of circulating metabolites on the QTc is largely unknown and limited to small studies. Purpose To test for association of circulating metabolites with the QTc interval in the UK Biobank study. Methods Participants were identified from the UK Biobank with same day plasma metabolite profiling and electrocardiograms. All 249 metabolites measured underwent quality control and log transformation to account for rightward skew and zero values. 149 metabolites with inter-correlations &amp;gt;0.7 were excluded. Participants taking QTc-prolonging medication or with a history of ischaemic heart disease or heart failure up to 6 months after the visit, were excluded. Participants were allocated to a training group (N=21,610) or an independent test group (N=5,304), if samples were obtained at recruitment or at a second visit, respectively. In the training group, each metabolite was tested separately for association with the QTc in linear regression analyses, adjusted for clinical covariates (age, sex, fasting time, body mass index (BMI), systolic blood pressure (SBP), smoking status, diabetes, lipid-lowering drug use and dietary factors). Significant metabolites (P&amp;lt;5x10-4) underwent validation in the test group. Sex-stratified analyses were also performed. In the training group, variables in two models underwent regularisation by LASSO regression (10-fold cross-validation) to reduce multicollinearity and downweigh less important variables; 1) clinical variables, 2) clinical variables and validated metabolites. Coefficients were used for QTc prediction in the test group. Significance between the models was evaluated by fisher’s transformation of R-squared statistics. Results In the per metabolite multivariate analysis, 56 metabolites were associated with the QTc interval. 19 metabolites validated in the test group. For 14 of these, absolute effect sizes were &amp;gt;5ms when comparing individuals in the top decile of the metabolite distribution verses the bottom (Figure 1), including the ketone body 3-hydroxybutyrate (9ms), and omega-6 fatty acid to total fatty acid ratio (7.2ms). For associations in males and females separately, significant effect size differences (P&amp;lt;0.05) were observed for 9 metabolites (Figure 2). In the training group, the combined LASSO model selected 17 (of 19) metabolites along with age, sex, SBP and BMI. In the test group, this model R-squared was 0.115 compared with 0.081 for clinical covariates alone, representing a significant 41.9% increase in QTc variation explained (P=0.002). Conclusions This study demonstrates clinically relevant metabolite associations with the QTc in individuals without cardiovascular disease and explain a significant proportion of QTc variation. Further investigation is warranted to test for direct effects on cardiac electrophysiology and proarrhythmic potential.Validated metabolitesSignificant sex differences

Can variants of genes associated with familial heart block predict conduction disease in the general population? A UK Biobank study.

Abstract Background Progressive familial heart block is a genetic disease that can present with worsening cardiac conduction disease (CCD) and risk of life-threatening bradycardia. The prevalence, penetrance, and expressivity of known rare pathogenic/likely pathogenic variants (P/LP) in the general population is unclear. In addition, the role of common genetic variation in this phenotypic expression is unknown. Understanding this is essential for patient management in clinic. Purpose 1). To investigate the prevalence of variants linked with early-onset CCD and phenotypic expression in a large biobank. 2). To investigate whether a PR interval polygenic risk score (PRS) improves risk prediction. Methods Early-onset conduction disease P/LP or variants of uncertain significance (VUS) were identified from ClinVar, genetic testing reports at a teaching hospital (6 variants), and the literature, mapping to 22 genes. From the full UK Biobank prospective cohort, 469,511 participants passed genetic quality control and were assigned to P/LP, VUS, or genotype negative (G-) groups, using whole exome sequencing analysed with bcftools. A PR-PRS was constructed using weights from a published meta-analysis excluding UKB data. The primary outcome was CCD (atrioventricular (AV) block, bundle branch block, pacemaker or ICD implantation) and secondary outcomes were high-grade AV block or pacemaker insertion, compared with lifetime risk Cox proportional hazards controlled for sex and age as a timescale. Results 55% of participants were female, 95% had European ancestry, and average age at censor was 71 years. There were 25 P/LP carriers, and 8,862 with a VUS, in 6 genes (MYH7, SCN5A, TNNI3K, TRPM4, TTN, and LMNA). Major demographic factors were the same between groups. CCD was significantly more prevalent in P/LP individuals (28% vs 5.8% in VUS vs 5.5% in G-; p&amp;lt;0.001) with a hazard ratio of HR 6.47 [95% CI=3.09-13.6] vs G-. This was driven by AV block and pacemaker implantation (HR 23.2 [95% CI=8.69-61.8] and 13.4 [95% CI=6.01-29.8], respectively). Results were similar in an unrelated subset and controlling for ischaemic heart disease and heart failure. The 7 P/LP individuals with conduction disease were mostly linked to a single LMNA variant (4 out of 6 carriers with penetrant disease). In the full cohort, the PR-PRS was predictive of CCD (HR=1.07 [95% CI=1.06-1.08]), AV block (HR=1.09 [95% CI=1.06-1.13]), and pacemaker implantation (HR=1.04 [95% CI=1.02-1.06]). When combined with P/LP status, both PR-PRS (HR=1.07 [95% CI=1.06-1.08]) and P/LP (HR=6.42 [95% CI=3.06-13.5]) were independent predictors of CCD. Conclusion(s) Rare variant carrier status predicts a 6.5-fold increased lifetime risk of CCD, a 23-fold increased risk of AV block and 13-fold risk for pacemaker requirement. However, phenotypic expression for some variants is highly variable. A PR-PRS captures risk independent of P/LP variants and warrants further investigation with updated PRS construction methods.

Association of a healthy plant-based heart-protective diet with reduced cardiovascular disease incidence and mortality: findings from the UK Biobank Study

Abstract Importance Previous research examining the effects of omnivorous and plant-based diets on CVD outcomes has produced inconsistent findings, and the importance of diet quality is overlooked. Objective To assess the relation between adherence to a healthy plant-based, heart-protective diet and the risk of cardiovascular disease (CVD) events. Design: Prospective cohort study. Methods and Results 192,274 (mean age: 56.3±7.9 years, 43.3% males) participants in UK Biobank without CVD at baseline who completed a 24-hour recall questionnaire. Using data generated by Oxford WebQ, we developed a novel heart-protective diet score (HPDS) based on 22 food groups. Cox proportional hazard models were used to study associations. During a median follow-up of 12.3 years, there were 20,692 CVD events and 1,131 CVD deaths. After adjusting for demographics, Townsend deprivation index, lifestyle factors, and history of chronic diseases, participants in the top quartile of the HPDS were at the lower risk of overall CVD (HR: 0.92, 95% CI: 0.88 to 0.95), ischemic heart disease (HR: 0.88 [95% CI: 0.83 to 0.93]), myocardial infarction (HR: 0.82, 95% CI: 0.74 to 0.90), and heart failure (HR: 0.86, 95% CI: 0.78 to 0.95) than those in the bottom quartile. Participants who adhered closely to a healthy plant-based heart-protective diet had the lowest risk of overall CVD (HR: 0.72, 95% CI: 0.61 to 0.86), ischemic heart disease (HR: 0.68, 95% CI: 0.52 to 0.89), myocardial infarction (HR: 0.65, 95% CI: 0.46 to 0.91), and heart failure (HR: 0.51, 95% CI: 0.30 to 0.85) mortality. Conclusions and relevance: Adherence to a healthy plant-based heart-protective diet rich in non-starchy vegetables, fruits, whole grains, legumes, and fish, is associated with a reduced cardiovascular disease incidence and mortality. Further research in diverse ethnic populations is necessary to validate our findings and enhance their generalizability.

Genetic and lifestyle risks for coronary artery disease and risk of incident dementia

Abstract Background Lifestyle risk factors for coronary artery disease (CAD) have been associated with neurodegeneration and dementia. Whether an underlying genetic risk for the development of CAD further increases this risk, however, remains unclear. Purpose To examine whether an increased genetic risk for CAD is associated with an increased risk of dementia, and to investigate whether lifestyle factors modify these associations. Methods A prospective cohort study of 457,353 participants of European ancestry without dementia at baseline (mean [SD], age 57 [8] years; 55% were female) was conducted within the UK Biobank study. Exposures were a genome-wide polygenic risk score (PRS) for CAD and a modified version of the American Heart Association’s Life’s Essential 8 (LE8) cardiovascular health score comprising four biological (BMI, BP, lipids, glucose) and four lifestyle (smoking status, diet, physical activity, and sleep duration) risk factors previously linked to both CAD and dementia. Dementia diagnoses were obtained from death register and inpatient records. Results 9,337 cases of all-cause dementia were observed over a median 13.9-year follow-up. There were no significant interactions between genetic risk for CAD and lifestyle factors for all-cause dementia, or any other dementia subtype. After adjusting for potential demographic confounders, a higher genetic risk for CAD was associated with elevated risk of developing all-cause dementia (hazard ratio (HR) per 1-SD increase in PRS = 1.08 [95% CI, 1.05-1.10]), Alzheimer’s disease (HR 1.08 [1.03-1.12]), and vascular dementia (HR 1.13 [1.06-1.19]). An unfavourable LE8 cardiovascular health score was also associated with an increased risk of developing all-cause dementia (HR 1.05 [1.02-1.08]), predominantly through its association with vascular dementia (HR 1.14 [1.06-1.22]), as we found no evidence for any associations between LE8 and Alzheimer’s disease (HR 1.00 [0.97-1.02]). Conclusion These findings indicate that a high genetic risk for CAD is associated with an increased risk of developing major dementia subtypes. Regardless of this underlying genetic risk, however, our results suggest that lifestyle interventions designed to reduce the risk of CAD may also reduce one’s risk of developing dementia, particularly in those with underlying vascular pathology.

Association of serum testosterone levels with left atrial size, function, and risk of atrial fibrillation in adult men: observational and mendelian randomization analyses

Abstract Background Numerous studies have investigated the association between serum testosterone levels, testosterone replacement therapy (TRT), and cardiovascular risk. However, research examining the relationship between testosterone levels and atrial fibrillation (AF) risk remains limited. We comprehensively analyzed the association between total testosterone (TT) levels, intermediary phenotypes such as left atrium (LA) size and function, and the risk of AF in middle-aged and older men. Methods We utilized data from the UK Biobank, a population-based prospective cohort, focusing on 179,988 White men who had complete serum TT level data and no AF history. Observational associations between TT levels and LA imaging traits, as well as AF risk, were estimated using multivariable regression and time-dependent Cox regression models, treating TT levels as a time-varying variable. Genetic associations were examined by Mendelian randomization (MR), using both UK Biobank and external large consortia genome-wide association study data. Results During the median follow-up of 11.8 years (IQR 10.9–12.5), we observed 13,847 incident AF cases (7.7%). Participants with normal TT levels (≥ 300 ng/dL) showed a 15% reduced risk of AF (HR of 0.85 [95% CI, 0.82–0.89]) compared to those with low TT (&amp;lt; 300 ng/dL). Interestingly, participants undergoing TRT experienced a 51% higher risk of AF (1.51 [1.09–2.07]). Furthermore, each 1-standard deviation increase in TT levels was associated with a reduced AF risk (OR of 0.91 [0.89–0.93]) and an improved LA emptying fraction (1.29 [1.06–1.58]). Applying age-specific cutoff values for low TT levels highlighted a more pronounced AF risk reduction in participants with normal TT. MR analyses supported these observations, suggesting potential causal relationships between TT levels and both LA function and AF risk. Conclusions Our findings suggest that low TT levels are associated with reduced LA function and increased risk of AF, both observationally and genetically, indicating that serum TT could serve as a surrogate marker or even a potential causal mediator in the development of AF.Abstract tableAbstract figure

Mapping renal impairment and cardiac structure and function: observation and genetic insights from 30,000 cardiac magnetic resonance images

Abstract Background The elevated risk of heart failure in kidney dysfunction is well-identified. However, the early alteration of renal impairment on cardiac structure and function, as well as genetic susceptibility associations have not been well reported. We sought to map the early effects of kidney dysfunction on cardiac remodeling with the cardiac magnetic resonance images (MRI) and identify share genetic correlation in community population. Methods Of 29,592 subjects underwent MRI test were recruited from the population-based UK Biobank study from 2006-2010. Renal function was assessed by historical identified chronic kidney disease (CKD), log-transfrom estimated glomerular filtration rate (eGFR) based on cystatin C (eGFRCysC) or serum creatine (eGFRSCr) and urine albumin-to-creatinine ratio (uACR). Multivariable generalized linear regression was used to analyse the association of 4 different kidney function indexes with six cardiac MRI-derived traits: left atria and ventricle, right atria and ventricle, and ascending and descending aortas. Genetic correlation between renal function decline and cardiac traits were evaluated by Mendelian randomization (MR). Results The mean (SD) age of subjects was 54.9 (7.5) years, and 51.1% were women. Observational and MR analysis showed a reliable relationship of lower level of eGFRCysC with reduced biventricular end systolic volume, biventricular ventricular end diastolic volume and left ventricular mass, and lower level of eGFRSCr with reduced left ventricular cardiac output. Conclusions Our study indicates the observational and genetic correlation between kidney function decline and cardiac measurements. These findings provide insights into the potential mechanisms behind their comorbidity and the future development of therapeutics.Renal function decline &amp; Cardiac Imaging

Population-Based Study of Rare Coding Variants in NR5A1/SF-1.

Steroidogenic Factor 1/Nuclear Receptor Subfamily 5 Group A Member 1 (SF-1/NR5A1) is critical for the development and function of sex organs, influencing steroidogenesis and reproduction. While rare deleterious NR5A1/SF-1 variants have been identified in individuals with various differences of sex development (DSD), primary ovarian insufficiency, and infertility, their impact on the general population remains unclear. We analyzed health records and exome sequencing data from up to 420 162 individuals (227 858 women) from the UK Biobank study to assess the impact of rare (frequency < 0.1%) predicted deleterious NR5A1/SF-1 variants on age at menopause and 26 other traits. No carriers of rare protein truncating variants in NR5A1/SF-1 were identified. We found that the previously reported association of rare deleterious missense NR5A1/SF-1 variants with earlier age at menopause is driven by variants in the DNA binding domain (DBD) and ligand binding domain (LBD) (combined test: beta = -2.36 years/allele, [95% CI: 3.21, -1.51], N = 107 carriers, P = 4.6 × 10-8). Carriers also had a higher risk of adult obesity (OR = 1.061, [95% CI: 1.003, 1.104], N = 344, P = .015), particularly among women (OR = 1.095 [95% CI: 1.034, 1.163, P = 3.87 × 10-3], N = 176), but not men (OR = 1.019, [95% CI: 0.955, 1.088], P = .57, N = 168). Deleterious missense variants in the DBD and LBD likely disrupt NR5A1/SF-1 function. This study broadens the relevance of deleterious NR5A1/SF-1 variants beyond rare DSDs, suggesting the need for extended phenotyping and monitoring of affected individuals.

Associations of body composition measures with circulating insulin-like growth factor-I, testosterone, and sex hormone-binding globulin concentrations in 16,000 men.

Adiposity is positively associated with risk of some cancer sites and other health conditions in men; however, it is unclear if endogenous hormones play a role in these associations. We examined how body composition, measured from magnetic resonance imaging (MRI) and common measures of adiposity (e.g., body mass index (BMI)), are related to hormone concentrations in men from the UK Biobank study. Up to 16,237 men with available body composition data (including visceral, subcutaneous, and liver fat, muscle fat infiltration (MFI), lean tissue, and common adiposity measures) and serum hormone measurements (insulin-like growth factor-I (IGF-I), total testosterone, sex hormone-binding globulin (SHBG), and calculated free testosterone) were included. Multivariable-adjusted linear regression models were used to determine the geometric mean hormone and SHBG concentrations across categories of each exposure. Common measurements of adiposity were highly correlated with MRI measures of central and total adiposity (r = 0.76-0.91), although correlations with ectopic fat (liver fat and MFI) were lower (r = 0.43-0.54). Most adiposity measurements showed an inverse U- or J-shaped association with circulating IGF-I and free testosterone; however, MFI was linearly inversely associated, and lean tissue volume was positively associated with both IGF-I and free testosterone concentrations. All body composition measures were inversely associated with total testosterone and SHBG concentrations (relative geometric mean difference between Q5 vs. Q1: 20-30%). Our results show that common adiposity and most MRI measures of adiposity relate similarly to serum hormone concentrations; however, associations with ectopic fat (particularly MFI) and lean tissue were different.