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Objective: To quantify the potential advantages of using 10 year risk prediction models for cardiovascular disease, in combination with risk thresholds specific to both age and sex, to identify individuals at high risk of cardiovascular disease for allocation of statin treatment. Design: Prospective open cohort study. Setting: Primary care data from the UK Clinical Practice Research Datalink GOLD, linked with hospital admissions from Hospital Episode Statistics and national mortality records from the Office for National Statistics in England, 1 January 2006 to 31 May 2019. Participants: 1 046 736 individuals (aged 40-85 years) with no cardiovascular disease, diabetes, or a history of statin treatment at baseline using data from electronic health records. Main outcome measures: 10 year risk of cardiovascular disease, calculated with version 2 of the QRISK cardiovascular disease risk algorithm (QRISK2), with two main strategies to identify individuals at high risk: in strategy A, estimated risk was a fixed cut-off value of ≥10% (ie, as per the UK National Institute for Health and Care Excellence guidelines); in strategy B, estimated risk was ≥10% or ≥90th centile of age and sex specific risk distributions. Results: Compared with strategy A, strategy B stratified 20 241 (149.8%) more women aged ≤53 years and 9832 (150.2%) more men aged ≤47 years as having a high risk of cardiovascular disease; for all other ages the strategies were the same. Assuming that treatment with statins would be initiated in those identified as high risk, differences in the estimated gain in cardiovascular disease-free life years from statin treatment for strategy B versus strategy A were 0.14 and 0.16 years for women and men aged 40 years, respectively; among individuals aged 40-49 years, the numbers needed to treat to prevent one cardiovascular disease event for strategy B versus strategy A were 39 versus 21 in women and 19 versus 15 in men, respectively. Conclusions: This study quantified the potential gains in cardiovascular disease-free life years when implementing prevention strategies based on age and sex specific risk thresholds instead of a fixed risk threshold for allocation of statin treatment. Such gains should be weighed against the costs of treating more younger people with statins for longer.
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The first dose of COVID-19 vaccines led to an overall reduction in cardiovascular events, and in rare cases, cardiovascular complications. There is less information about the effect of second and booster doses on cardiovascular diseases. Using longitudinal health records from 45.7 million adults in England between December 2020 and January 2022, our study compared the incidence of thrombotic and cardiovascular complications up to 26 weeks after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA-1273). These findings support the wide uptake of future COVID-19 vaccination programs.
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Vacunas contra la COVID-19 , COVID-19 , Enfermedades Cardiovasculares , Vacunación , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vacuna nCoV-2019 mRNA-1273/administración & dosificación , Vacuna nCoV-2019 mRNA-1273/efectos adversos , Vacuna BNT162/efectos adversos , Vacuna BNT162/administración & dosificación , Enfermedades Cardiovasculares/epidemiología , ChAdOx1 nCoV-19/administración & dosificación , ChAdOx1 nCoV-19/efectos adversos , Estudios de Cohortes , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , Inglaterra/epidemiología , Inmunización Secundaria/efectos adversos , Incidencia , Infarto del Miocardio/epidemiología , Infarto del Miocardio/etiología , Miocarditis/epidemiología , Miocarditis/etiología , Embolia Pulmonar/epidemiología , Embolia Pulmonar/etiología , Trombosis/epidemiología , Trombosis/etiología , Vacunación/efectos adversos , Adolescente , Adulto Joven , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates has not been quantified. METHODS: We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1 (forced expiratory volume in 1 s) trajectories and FEV1 within-individual variability as a function of sex, age at annual review, diagnosis after first year of life, homozygous F508 genotype and birth cohort. RESULTS: Mean FEV1 decreased with age and lung function variability showed a near-quadratic trend by age. Males showed higher FEV1 mean and variability than females across the whole age range. Earlier diagnosis and homozygous F508 genotype were also associated with higher FEV1 mean and variability. Individuals who died during follow-up showed on average higher lung function variability than those who survived. CONCLUSIONS: Key variables known to be linked with mean lung function in cystic fibrosis are also associated with an individual's lung function variability. This work opens new avenues to understand the role played by lung function variability in disease progression and its utility in predicting key outcomes such as mortality.
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Infection with SARS-CoV-2 is associated with an increased risk of arterial and venous thrombotic events, but the implications of vaccination for this increased risk are uncertain. With the approval of NHS England, we quantified associations between COVID-19 diagnosis and cardiovascular diseases in different vaccination and variant eras using linked electronic health records for ~40% of the English population. We defined a 'pre-vaccination' cohort (18,210,937 people) in the wild-type/Alpha variant eras (January 2020-June 2021), and 'vaccinated' and 'unvaccinated' cohorts (13,572,399 and 3,161,485 people respectively) in the Delta variant era (June-December 2021). We showed that the incidence of each arterial thrombotic, venous thrombotic and other cardiovascular outcomes was substantially elevated during weeks 1-4 after COVID-19, compared with before or without COVID-19, but less markedly elevated in time periods beyond week 4. Hazard ratios were higher after hospitalised than non-hospitalised COVID-19 and higher in the pre-vaccination and unvaccinated cohorts than the vaccinated cohort. COVID-19 vaccination reduces the risk of cardiovascular events after COVID-19 infection. People who had COVID-19 before or without being vaccinated are at higher risk of cardiovascular events for at least two years.
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COVID-19 , Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/epidemiología , COVID-19/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , Prueba de COVID-19 , Vacunas contra la COVID-19 , Estudios de Cohortes , VacunaciónRESUMEN
Importance: Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive. Objectives: To investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations. Design, Setting, and Participants: This genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023. Exposures: Genetically predicted apoB, LDL-C, and TG. Main Outcomes and Measures: The primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality. Results: This study included 347â¯797 participants (mean [SD] age, 57.2 [8.0] years; 188â¯330 female [54.1%]). There were 23â¯818 people who developed CAD and 23â¯848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age. Conclusions and relevance: In this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.
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Enfermedad de la Arteria Coronaria , Humanos , Masculino , Femenino , Persona de Mediana Edad , Enfermedad de la Arteria Coronaria/genética , LDL-Colesterol/genética , Factores de Riesgo , Apolipoproteínas B , TriglicéridosRESUMEN
BACKGROUND: Insulin resistance is a hypothesised biological mechanism linking obesity with prostate cancer (PCa) death. Data in support of this hypothesis is limited. METHODS: We included 259,884 men from eight European cohorts, with 11,760 incident PCa's and 1784 PCa deaths during follow-up. We used the triglyceride-glucose (TyG) index as indicator of insulin resistance. We analysed PCa cases with follow-up from PCa diagnosis, and the full cohort with follow-up from the baseline cancer-free state, thus incorporating both PCa incidence and death. We calculated hazard ratios (HR) and the proportion of the total effect of body mass index (BMI) on PCa death mediated through TyG index. RESULTS: In the PCa-case-only analysis, baseline TyG index was positively associated with PCa death (HR per 1-standard deviation: 1.11, 95% confidence interval (CI); 1.01-1.22), and mediated a substantial proportion of the baseline BMI effect on PCa death (HRtotal effect per 5-kg/m2 BMI: 1.24; 1.14-1.35, of which 28%; 4%-52%, mediated). In contrast, in the full cohort, the TyG index was not associated with PCa death (HR: 1.03; 0.94-1.13), hence did not substantially mediate the effect of BMI on PCa death. CONCLUSIONS: Insulin resistance could be an important pathway through which obesity accelerates PCa progression to death.
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Resistencia a la Insulina , Neoplasias de la Próstata , Masculino , Humanos , Índice de Masa Corporal , Análisis de Mediación , Glucosa , Obesidad/complicaciones , Obesidad/epidemiología , Triglicéridos , Glucemia , Factores de Riesgo , BiomarcadoresRESUMEN
OBJECTIVE: To provide quantitative evidence for systematically prioritising individuals for full formal cardiovascular disease (CVD) risk assessment using primary care records with a novel tool (eHEART) with age- and sex- specific risk thresholds. METHODS AND ANALYSIS: eHEART was derived using landmark Cox models for incident CVD with repeated measures of conventional CVD risk predictors in 1,642,498 individuals from the Clinical Practice Research Datalink. Using 119,137 individuals from UK Biobank, we modelled the implications of initiating guideline-recommended statin therapy using eHEART with age- and sex-specific prioritisation thresholds corresponding to 5% false negative rates to prioritise adults aged 40-69 years in a population in England for invitation to a formal CVD risk assessment. RESULTS: Formal CVD risk assessment on all adults would identify 76% and 49% of future CVD events amongst men and women respectively, and 93 (95% CI: 90, 95) men and 279 (95% CI: 259, 297) women would need to be screened (NNS) to prevent one CVD event. In contrast, if eHEART was first used to prioritise individuals for formal CVD risk assessment, we would identify 73% and 47% of future events amongst men and women respectively, and a NNS of 75 (95% CI: 72, 77) men and 162 (95% CI: 150, 172) women. Replacing the age- and sex-specific prioritisation thresholds with a 10% threshold identify around 10% less events. CONCLUSIONS: The use of prioritisation tools with age- and sex-specific thresholds could lead to more efficient CVD assessment programmes with only small reductions in effectiveness at preventing new CVD events.
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Enfermedades Cardiovasculares , Adulto , Masculino , Humanos , Femenino , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Inglaterra/epidemiología , Medición de Riesgo , Atención Primaria de Salud , Factores de RiesgoRESUMEN
BACKGROUND: Vasovagal reactions (VVRs) are the most common acute complications of blood donation. Responsible for substantial morbidity, they also reduce the likelihood of repeated donations and are disruptive and costly for blood services. Although blood establishments worldwide have adopted different strategies to prevent VVRs (including water loading and applied muscle tension [AMT]), robust evidence is limited. The Strategies to Improve Donor Experiences (STRIDES) trial aims to reliably assess the impact of four different interventions to prevent VVRs among blood donors. METHODS: STRIDES is a cluster-randomised cross-over/stepped-wedge factorial trial of four interventions to reduce VVRs involving about 1.4 million whole blood donors enrolled from all 73 blood donation sites (mobile teams and donor centres) of National Health Service Blood and Transplant (NHSBT) in England. Each site ("cluster") has been randomly allocated to receive one or more interventions during a 36-month period, using principles of cross-over, stepped-wedge and factorial trial design to assign the sequence of interventions. Each of the four interventions is compared to NHSBT's current practices: (i) 500-ml isotonic drink before donation (vs current 500-ml plain water); (ii) 3-min rest on donation chair after donation (vs current 2 min); (iii) new modified AMT (vs current practice of AMT); and (iv) psychosocial intervention using preparatory materials (vs current practice of nothing). The primary outcome is the number of in-session VVRs with loss of consciousness (i.e. episodes involving loss of consciousness of any duration, with or without additional complications). Secondary outcomes include all in-session VVRs (i.e. with and without loss of consciousness), all delayed VVRs (i.e. those occurring after leaving the venue) and any in-session non-VVR adverse events or reactions. DISCUSSION: The STRIDES trial should yield novel information about interventions, singly and in combination, for the prevention of VVRs, with the aim of generating policy-shaping evidence to help inform blood services to improve donor health, donor experience, and service efficiency. TRIAL REGISTRATION: ISRCTN: 10412338. Registration date: October 24, 2019.
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Donantes de Sangre , Síncope Vasovagal , Humanos , Medicina Estatal , Síncope Vasovagal/diagnóstico , Síncope Vasovagal/etiología , Síncope Vasovagal/prevención & control , Agua , Donación de SangreRESUMEN
Background The aim of this study was to provide quantitative evidence of the use of polygenic risk scores for systematically identifying individuals for invitation for full formal cardiovascular disease (CVD) risk assessment. Methods and Results A total of 108 685 participants aged 40 to 69 years, with measured biomarkers, linked primary care records, and genetic data in UK Biobank were used for model derivation and population health modeling. Prioritization tools using age, polygenic risk scores for coronary artery disease and stroke, and conventional risk factors for CVD available within longitudinal primary care records were derived using sex-specific Cox models. We modeled the implications of initiating guideline-recommended statin therapy after prioritizing individuals for invitation to a formal CVD risk assessment. If primary care records were used to prioritize individuals for formal risk assessment using age- and sex-specific thresholds corresponding to 5% false-negative rates, then the numbers of men and women needed to be screened to prevent 1 CVD event are 149 and 280, respectively. In contrast, adding polygenic risk scores to both prioritization and formal assessments, and selecting thresholds to capture the same number of events, resulted in a number needed to screen of 116 for men and 180 for women. Conclusions Using both polygenic risk scores and primary care records to prioritize individuals at highest risk of a CVD event for a formal CVD risk assessment can efficiently prioritize those who need interventions the most than using primary care records alone. This could lead to better allocation of resources by reducing the number of risk assessments in primary care while still preventing the same number of CVD events.
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Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Accidente Cerebrovascular , Masculino , Humanos , Femenino , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Factores de Riesgo , Enfermedad de la Arteria Coronaria/complicaciones , Medición de Riesgo/métodos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/prevención & controlRESUMEN
This retrospective cohort study investigated the incidence and risk factors of major adverse cardiovascular events (MACE) after 1 year of first-documented myocardial infarctions (MIs) in a multi-ethnic Asian population. Secondary MACE were observed in 231 (14.3%) individuals, including 92 (5.7%) cardiovascular-related deaths. Both histories of hypertension and diabetes were associated with secondary MACE after adjustment for age, sex, and ethnicity (HR 1.60 [95%CI 1.22-2.12] and 1.46 [95%CI 1.09-1.97], respectively). With further adjustments for traditional risk factors, individuals with conduction disturbances demonstrated higher risks of MACE: new left-bundle branch block (HR 2.86 [95%CI 1.15-6.55]), right-bundle branch block (HR 2.09 [95%CI 1.02-4.29]), and second-degree heart block (HR 2.45 [95%CI 0.59-10.16]). These associations were broadly similar across different age, sex, and ethnicity groups, although somewhat greater for history of hypertension and BMI among women versus men, for HbA1c control in individuals aged >50 years, and for LVEF ≤ 40% in those with Indian versus Chinese or Bumiputera ethnicities. Several traditional and cardiac risk factors are associated with a higher risk of secondary major adverse cardiovascular events. In addition to hypertension and diabetes, the identification of conduction disturbances in individuals with first-onset MI may be useful for the risk stratification of high-risk individuals.
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BACKGROUND: Deferrals due to low hemoglobin are time-consuming and costly for blood donors and donation services. Furthermore, accepting donations from those with low hemoglobin could represent a significant safety issue. One approach to reduce them is to use hemoglobin concentration alongside donor characteristics to inform personalized inter-donation intervals. STUDY DESIGN AND METHODS: We used data from 17,308 donors to inform a discrete event simulation model comparing personalized inter-donation intervals using "post-donation" testing (i.e., estimating current hemoglobin from that measured by a hematology analyzer at last donation) versus the current approach in England (i.e., pre-donation testing with fixed intervals of 12-weeks for men and 16-weeks for women). We reported the impact on total donations, low hemoglobin deferrals, inappropriate bleeds, and blood service costs. Personalized inter-donation intervals were defined using mixed-effects modeling to estimate hemoglobin trajectories and probability of crossing hemoglobin donation thresholds. RESULTS: The model had generally good internal validation, with predicted events similar to those observed. Over 1 year, a personalized strategy requiring ≥90% probability of being over the hemoglobin threshold, minimized adverse events (low hemoglobin deferrals and inappropriate bleeds) in both sexes and costs in women. Donations per adverse event improved from 3.4 (95% uncertainty interval 2.8, 3.7) under the current strategy to 14.8 (11.6, 19.2) in women, and from 7.1 (6.1, 8.5) to 26.9 (20.8, 42.6) in men. In comparison, a strategy incorporating early returns for those with high certainty of being over the threshold maximized total donations in both men and women, but was less favorable in terms of adverse events, with 8.4 donations per adverse event in women (7.0, 10,1) and 14.8 (12.1, 21.0) in men. DISCUSSION: Personalized inter-donation intervals using post-donation testing combined with modeling of hemoglobin trajectories can help reduce deferrals, inappropriate bleeds, and costs.
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Donación de Sangre , Hemoglobinas , Masculino , Humanos , Femenino , Hemoglobinas/análisis , Inglaterra , Pruebas Hematológicas , Donantes de SangreRESUMEN
Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
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Errores Innatos del Metabolismo , Metaboloma , Humanos , Metaboloma/genética , Metabolómica , Plasma/metabolismo , Fenotipo , Errores Innatos del Metabolismo/genética , Proteínas de la Membrana/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismoRESUMEN
BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.
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COVID-19 , Trombosis , Enfermedades Vasculares , Tromboembolia Venosa , Trombosis de la Vena , Adulto , COVID-19/complicaciones , COVID-19/epidemiología , Vacunas contra la COVID-19 , Estudios de Cohortes , Humanos , SARS-CoV-2 , Trombosis/complicaciones , Trombosis/epidemiología , Enfermedades Vasculares/complicaciones , Tromboembolia Venosa/etiología , Trombosis de la Vena/epidemiología , Gales/epidemiologíaRESUMEN
BACKGROUND: Cardiovascular disease (CVD) risk prediction models for individuals with type 2 diabetes are important tools to guide intensification of interventions for CVD prevention. We aimed to assess the added value of incorporating risk factors variability in CVD risk prediction for people with type 2 diabetes. METHODS: We used electronic health records (EHRs) data from 83â910 adults with type 2 diabetes but without pre-existing CVD from the UK Clinical Practice Research Datalink for 2004-2017. Using a landmark-modelling approach, we developed and validated sex-specific Cox models, incorporating conventional predictors and trajectories plus variability of systolic blood pressure (SBP), total and high-density lipoprotein (HDL) cholesterol, and glycated haemoglobin (HbA1c). Such models were compared against simpler models using single last observed values or means. RESULTS: The standard deviations (SDs) of SBP, HDL cholesterol and HbA1c were associated with higher CVD risk (P < 0.05). Models incorporating trajectories and variability of continuous predictors demonstrated improvement in risk discrimination (C-index = 0.659, 95% CI: 0.654-0.663) as compared with using last observed values (C-index = 0.651, 95% CI: 0.646-0.656) or means (C-index = 0.650, 95% CI: 0.645-0.655). Inclusion of SDs of SBP yielded the greatest improvement in discrimination (C-index increase = 0.005, 95% CI: 0.004-0.007) in comparison to incorporating SDs of total cholesterol (C-index increase = 0.002, 95% CI: 0.000-0.003), HbA1c (C-index increase = 0.002, 95% CI: 0.000-0.003) or HDL cholesterol (C-index increase= 0.003, 95% CI: 0.002-0.005). CONCLUSION: Incorporating variability of predictors from EHRs provides a modest improvement in CVD risk discrimination for individuals with type 2 diabetes. Given that repeat measures are readily available in EHRs especially for regularly monitored patients with diabetes, this improvement could easily be achieved.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Adulto , Masculino , Femenino , Humanos , Factores de Riesgo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , HDL-Colesterol , Hemoglobina Glucada , Registros Electrónicos de Salud , Factores de Riesgo de Enfermedad Cardiaca , Atención Primaria de Salud , Reino Unido/epidemiologíaRESUMEN
Background: Telomere length is associated with risk of several age-related diseases and cancers. We aimed to investigate the extent to which telomere length might be modifiable through lifestyle and behaviour, and whether such modification has any clinical consequences. Methods: In this population-based study, we included participants from UK Biobank who had leukocyte telomere length (LTL) measurement, ethnicity, and white blood cell count data. We investigated associations of LTL with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating between them smoking, physical activity, diet, maintenance of a healthy bodyweight, and alcohol intake, using both available and imputed data. To help interpretation, associations were summarised as the number of equivalent years of age-related change in LTL by dividing the trait ß coefficients with the age ß coefficient. We used mendelian randomisation to test causality of selected associations. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease might be mediated through LTL. Findings: 422â797 participants were available for the analysis (227â620 [53·8%] were women and 400â036 [94·6%] were White). 71 traits showed significant (p<4·27â×â10-4) associations with LTL but most were modest, equivalent to less than 1 year of age-related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to ≥2 years of age-related change in LTL), oily fish intake, educational attainment, and general health status retained a significant association of this magnitude, with walking pace and current smoking being additionally significant at this level of association in the imputed models. Mendelian randomisation analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the most healthy behaviours having longer LTL equivalent to about 3·5 years of age-related change in LTL than those with the least heathy behaviours (p<0·001). However, healthy behaviours explained less than 0·2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of coronary artery disease were substantially mediated through LTL. Interpretation: Although several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Attempts to change telomere length through lifestyle or behavioural changes might not confer substantial clinical benefit. Funding: UK Medical Research Council, UK Biotechnology and Biological Sciences Research Council, and British Heart Foundation.
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Enfermedad de la Arteria Coronaria , Telómero , Bancos de Muestras Biológicas , Femenino , Conductas Relacionadas con la Salud , Estado de Salud , Humanos , Leucocitos , Masculino , Análisis de la Aleatorización Mendeliana , Reino UnidoRESUMEN
BACKGROUND: Frailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, inter-individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty. METHODS: We utilized cross-sectional data from 441 781 UK Biobank participants (aged 40-69 years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2 weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single-copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal. RESULTS: Frail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P = 2.73 × 10-33 ), more likely to be female (61%, P = 1.97 × 10-129 ), and had shorter LTL (-0.13SD vs. 0.03SD, P = 5.43 × 10-111 ) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (RRR = 1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P = 3.99 × 10-12 ; 1.10 (1.08; 1.11) per SD shorter LTL, P = 1.46 × 10-30 ). Within each age group (40-49, 50-59, 60-69 years), the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR-Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P = 0.13). CONCLUSIONS: Inter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.
Asunto(s)
Fragilidad , Adulto , Estudios Transversales , Femenino , Fragilidad/epidemiología , Fragilidad/genética , Humanos , Leucocitos , Masculino , Factores de Riesgo , Telómero/genéticaRESUMEN
BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. MAIN OUTCOME MEASURES: CHD, CHD risk factors, and ANM. RESULTS: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVWâ =â 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.
Asunto(s)
Enfermedad Coronaria , Estudio de Asociación del Genoma Completo , Envejecimiento/genética , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: To evaluate antithrombotic (AT) use in individuals with atrial fibrillation (AF) and at high risk of stroke (CHA2DS2-VASc score ≥2) and investigate whether pre-existing AT use may improve COVID-19 outcomes. METHODS: Individuals with AF and CHA2DS2-VASc score ≥2 on 1 January 2020 were identified using electronic health records for 56 million people in England and were followed up until 1 May 2021. Factors associated with pre-existing AT use were analysed using logistic regression. Differences in COVID-19-related hospitalisation and death were analysed using logistic and Cox regression in individuals with pre-existing AT use versus no AT use, anticoagulants (AC) versus antiplatelets (AP), and direct oral anticoagulants (DOACs) versus warfarin. RESULTS: From 972 971 individuals with AF (age 79 (±9.3), female 46.2%) and CHA2DS2-VASc score ≥2, 88.0% (n=856 336) had pre-existing AT use, 3.8% (n=37 418) had a COVID-19 hospitalisation and 2.2% (n=21 116) died, followed up to 1 May 2021. Factors associated with no AT use included comorbidities that may contraindicate AT use (liver disease and history of falls) and demographics (socioeconomic status and ethnicity). Pre-existing AT use was associated with lower odds of death (OR=0.92, 95% CI 0.87 to 0.96), but higher odds of hospitalisation (OR=1.20, 95% CI 1.15 to 1.26). AC versus AP was associated with lower odds of death (OR=0.93, 95% CI 0.87 to 0.98) and higher hospitalisation (OR=1.17, 95% CI 1.11 to 1.24). For DOACs versus warfarin, lower odds were observed for hospitalisation (OR=0.86, 95% CI 0.82 to 0.89) but not for death (OR=1.00, 95% CI 0.95 to 1.05). CONCLUSIONS: Pre-existing AT use may be associated with lower odds of COVID-19 death and, while not evidence of causality, provides further incentive to improve AT coverage for eligible individuals with AF.