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Researchers develop a heart ‘fingerprint’ to tailor personalised treatments.
Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.
Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P
Neuroticism, omega-3 fatty acids, and risk of incident dementia.
BACKGROUND: High levels of neuroticism are associated with an increased risk of dementia, yet the underlying biological mechanisms remain poorly understood. Investigating the role of metabolites, the downstream products of metabolic processes, may offer valuable insights into this association. METHODS: In 215,624 dementia-free UK Biobank participants aged 40-69 years, we assessed neuroticism's associations with 249 nuclear magnetic resonance-measured metabolites using linear regression. Metabolites reaching Bonferroni-corrected significance were further tested for associations with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VaD) using Cox proportional-hazards regression, and with white matter hyperintensities volume using linear regression. Causality in significant observational relationships was evaluated through two-sample Mendelian randomization. RESULTS: Neuroticism was significantly associated with 119 out of 249 metabolites (Bonferroni-adjusted p
GWAS meta-analysis of CSF Alzheimer's disease biomarkers 18,948 individuals reveal novel loci and genes regulating lipid metabolism, brain volume and autophagy.
Cerebrospinal fluid (CSF) amyloid beta (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau181) are well accepted markers of Alzheimer's disease. We performed a GWAS meta-analysis including 18,948 individuals of European and 416 non-European ancestry. We identified 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicated the association of CSF biomarkers with APOE , CR1 , GMNC/CCDC50 and C16orf95/MAP1LC3B . Novel loci included BIN1 for Aβ42 and GNA12, MS4A6A, SLCO1A2 with both t-tau and p-tau181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2 . We also demonstrated that these variants were not only associated with CSF level of the three biomarkers but also showed significant association with AD risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent APOE , as well as autophagy and brain volume regulation driven by t-tau and p-tau181 dysregulation.
Associations Between Trust in Healthcare Professionals and Perceptions of Modifiability of Dementia and Stroke Risks Through Maintaining or Changing Lifestyle Habits
Purpose: To investigate the trust levels in health information sources from a United States (U.S.) sample, and to examine the relationships between trust in healthcare professionals (HCPs) and perceptions of modifiability of dementia and stroke risks through maintaining or changing lifestyle habits. Design: Cross-sectional. Setting: A survey distributed via the vendor platform Prolific to a sample of the U.S. population. Participants: Data included on U.S. adults (n = 1478) in 2023. Measures: Outcome variables were perceiving that dementia and stroke risk can be modified through maintaining or changing lifestyle habits. Independent variables were trust levels in HCPs. Analysis: Descriptive analysis was performed to assess levels of trust in information sources. Subsequently, we performed multivariable regression analyses between trust in HCPs and perceptions of risk modifiability in dementia and stroke. A hierarchal cluster analysis was conducted to characterize trust patterns in this cohort. Results: Participants with high trust in HCPs compared to those with low trust in HCPs were more likely to perceive that maintaining (adjusted odds ratio [aOR] = 1.57, 95% confidence interval [CI]:1.15-2.12) and changing lifestyle habits (aOR = 1.72, 95% CI: 1.26-2.33) could reduce risk of dementia. Similar associations were found for perceptions of stroke risk reduction through maintaining (aOR = 1.49, 95% CI: 1.07-2.04) and changing (aOR = 2.68, 95% CI: 1.72-4.12) lifestyle habits. Cluster analyses identified three trust patterns amongst the participants: (i) a generally trusting cluster, (ii) a trusting of “official” health sources only cluster, and (iii) a generally not trusting cluster. Conclusion: This study found statistically significant associations between trusting HCPs and the perceptions that maintaining or changing lifestyle habits can modify risks of dementia and stroke, highlighting the importance of trust when developing preventive strategies.
Association of Daily Steps with Incident Non-Alcoholic Fatty Liver Disease: Evidence from the UK Biobank Cohort.
PURPOSE: Low physical activity has been shown to be associated with higher risk of non-alcoholic fatty liver disease (NAFLD). However, the strength and shape of this association are currently uncertain due to a reliance on self-reported physical activity measures. This report aims to investigate the relationship of median daily step count with NAFLD using accelerometer-derived step count from a large prospective cohort study. METHODS: The wrist-worn accelerometer sub-study of the UK Biobank (N = ~100,000) was used to characterise median daily step count over a seven-day period. NAFLD cases were ascertained via record linkage with hospital inpatient data and death registers or by using a measure of liver fat from imaging. Cox proportional hazards models were employed to assess the association between step count and NAFLD, adjusting for age, sociodemographic, and lifestyle factors. Mediation analyses were conducted. RESULTS: Among 91,031 participants (709,440 person-years of follow-up), there were 762 incident NAFLD cases. Higher step count was log-linearly and inversely associated with risk of NAFLD. A 1000-step increase (representing 10 minutes of walking) was associated with a 12% (95% CI: 10%-14%) lower hazard of NAFLD. When using imaging to identify NAFLD, a 1,000-step increase was associated with a 6% (95% CI: 6%-7%) lower risk. There was evidence for mediation by adiposity, accounting for 39% of the observed association. CONCLUSIONS: Daily step count, a modifiable risk factor, is log-linearly and inversely associated with NAFLD. This association was only partially explained by adiposity. These findings from a large cohort study may have important implications for strategies to lower NAFLD risk.
Consensus recommendations for hyperpolarized [1-13C]pyruvate MRI multi-center human studies.
MRI of hyperpolarized (HP) [1-13C]pyruvate allows in vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. To determine consensus on best practice for multi-center studies for development of clinical applications. This paper presents the results of a two-round formal consensus building exercise carried out by experts with HP [1-13C]pyruvate human study experience. Twenty-nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data analysis with the goal of providing recommendations and best practice statements on conduct of multi-center human studies of HP [1-13C]pyruvate MRI. Overall, the group reached consensus on approximately two-thirds of 246 statements in the questionnaire, covering HP 13C-pyruvate preparation; MRI system setup, calibration, and phantoms; acquisition and reconstruction; and data analysis and quantification. Consensus was present across categories. Examples include: (i) Different HP pyruvate preparation methods could be used in human studies, but the same release criteria have to be followed; (ii) site qualification and quality assurance must be performed with phantoms and the same field strength must be used, but the rest of the system setup and calibration methods could be determined by individual sites; (iii) the same pulse sequence and reconstruction methods were preferable, but the exact choice should be governed by the anatomical target; (iv) normalized metabolite area-under-curve values and metabolite area under curve were the preferred metabolism metrics. The consensus proces revealed that HP[1-13C] pyruvate MRI as a technology has progressed sufficiently to plan multi-center studies. The work confirmed areas of consensus for multi-center study conduct and identified where further research is required to ascertain best practice.
Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes
Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes, but these variants have proven challenging to detect. Genome-wide association studies of monozygotic twin differences are conducted through family-based variance analyses, which are more robust to the systemic biases that impact population-based methods. We combined data from 21,792 monozygotic twins (10,896 pairs) from 11 studies to conduct one of the largest genome-wide association study meta-analyses of monozygotic phenotypic differences, in children, adolescents and adults separately, for seven psychiatric and neurodevelopmental phenotypes: attention deficit hyperactivity disorder symptoms, autistic traits, anxiety and depression symptoms, psychotic-like experiences, neuroticism and wellbeing. The proportions of phenotypic variance explained by single-nucleotide polymorphisms in these phenotypes were estimated (h2 = 0–18%), but were imprecise. We identified 13 genome-wide significant associations (single-nucleotide polymorphisms, genes and gene sets), including genes related to stress reactivity for depression, growth factor-related genes for autistic traits and catecholamine uptake-related genes for psychotic-like experiences. This is the largest genetic study of monozygotic twins to date by an order of magnitude, evidencing an alternative method to study the genetic architecture of environmental sensitivity. The statistical power was limited for some analyses, calling for better-powered future studies.
The impact of estrogen deficiency on liver metabolism; implications for hormone replacement therapy
Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD) is the most common chronic liver condition globally. It affects 1-in-3 individuals and is associated with increased liver and cardiovascular mortality. MASLD is a sexually dimorphic condition and in women the prevalence and severity of MASLD rises significantly following menopause. Preclinical data shows that lack of estrogen promotes multisystem metabolic dysfunction that is characteristic of MASLD. This not only includes hepatic lipid accumulation, insulin resistance and fibrosis, but also extra-hepatic metabolic processes in adipose and skeletal muscle. There are currently no available MASLD treatments tailored to women. The uptake of estrogen-based menopausal hormone replacement therapy (HRT) has seen a dramatic increase in recent years. Despite the changing attitudes to HRT and the strong evidence base implicating estrogen deficiency in the development of MASLD, the impact of HRT on MASLD in postmenopausal women is poorly studied. In this review, we discuss the burden of MASLD in women, the effect of estrogen deficiency on the processes that drive MASLD development and progression, and explore potential sex-specific therapeutic strategies that may prevent or limit MASLD development after menopause.
Cohort profile: characterisation, determinants, mechanisms and consequences of the long-term effects of COVID-19 - providing the evidence base for health care services (CONVALESCENCE) in the UK.
PURPOSE: The pathogenesis of the long-lasting symptoms which can follow an infection with the SARS-CoV-2 virus ('long covid') is not fully understood. The 'COroNaVirus post-Acute Long-term EffectS: Constructing an evidENCE base' (CONVALESCENCE) study was established as part of the Longitudinal Health and Wellbeing COVID-19 UK National Core Study. We performed a deep phenotyping case-control study nested within two cohorts (the Avon Longitudinal Study of Parents and Children and TwinsUK) as part of CONVALESCENCE. PARTICIPANTS: From September 2021 to May 2023, 349 participants attended the CONVALESCENCE deep phenotyping clinic at University College London. Four categories of participants were recruited: cases of long covid (long covid(+)/SARS-CoV-2(+)), alongside three control groups: those with neither long covid symptoms nor evidence of prior COVID-19 (long covid(-)/SARS-CoV-2(-); control group 1), those who self-reported COVID-19 and had evidence of SARS-CoV-2 infection, but did not report long covid (long covid(-)/SARS-CoV-2(+); control group 2) and those who self-reported persistent symptoms attributable to COVID-19 but no evidence of SARS-CoV-2 infection (long covid(+)/SARS-CoV-2(-); control group 3). Remote wearable measurements were performed up until February 2024. FINDINGS TO DATE: This cohort profile describes the baseline characteristics of the CONVALESCENCE cohort. Of the 349 participants, 141 (53±15 years old; 21 (15%) men) were cases, 89 (55±16 years old; 11 (12%) men) were in control group 1, 75 (49±15 years old; 25 (33%) men) were in control group 2 and 44 (55±16 years old; 9 (21%) men) were in control group 3. FUTURE PLANS: The study aims to use a multiorgan score calculated as the cumulative total for each of nine domains (ie, lung, vascular, heart, kidney, brain, autonomic function, muscle strength, exercise capacity and physical performance). The availability of data preceding acute COVID-19 infection in cohorts may help identify the consequences of infection independent of pre-existing subclinical disease and also provide evidence of determinants that influence the development of long covid.
Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.
A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.
Mechanistic Pathways Underlying Genetic Predisposition to Atrial Fibrillation Are Associated With Different Cardiac Phenotypes and Cardioembolic Stroke Risk.
BACKGROUND: Genome-wide association studies have clustered candidate genes associated with atrial fibrillation (AF) into biological pathways reflecting different pathophysiological mechanisms. We investigated whether these pathways associate with distinct intermediate phenotypes and confer differing risks of cardioembolic stroke. METHODS: Three distinct subsets of AF-associated genetic variants, each representing a different mechanistic pathway, that is, the cardiac muscle function and integrity pathway (15 variants), the cardiac developmental pathway (25 variants), and the cardiac ion channels pathway (12 variants), were identified from previous AF genome-wide association studies. Using genetic epidemiological methods and large-scale datasets such as UK Biobank, deCODE, and GIGASTROKE, we investigated the associations of these pathways with AF-related cardiac intermediate phenotypes, which included electrocardiogram parameters (≈16 500 electrocardiograms), left atrial and ventricular size and function (≈36 000 cardiac magnetic resonance imaging scans), and relevant plasma biomarkers (N-terminal pro-B-type natriuretic peptide, ≈70 000 samples; high-sensitivity troponin I and T, ≈87 000 samples), as well as with subtypes of ischemic stroke (≈11 000 cases). RESULTS: Genetic variants representing distinct AF-related mechanistic pathways had significantly different effects on several AF-related phenotypes. In particular, the muscle pathway was associated with a longer PR interval (P for heterogeneity between pathways [Phet]=1×10-10), lower left atrial emptying fraction (Phet=5×10-5), and higher N-terminal pro-B-type natriuretic peptide (Phet=2×10-3) per log-odds higher risk of AF compared with the developmental and ion-channel pathways. In contrast, the ion-channel pathway was associated with a lower risk of cardioembolic stroke (Phet=0.04 in European, and 7×10-3 in multiancestry populations) compared with the other pathways. CONCLUSIONS: Genetic variants representing specific mechanistic pathways for AF are associated with distinct intermediate cardiac phenotypes and a different risk of cardioembolic stroke. These findings provide a better understanding of the etiological heterogeneity underlying the development of AF and its downstream impact on disease and may offer a route to more targeted treatment strategies.
An application of the MR-Horse method to reduce selection bias in genome-wide association studies of disease progression
Genome-wide association studies (GWAS) of disease progression are vulnerable to collider bias caused by selection of participants with disease at study entry. This bias introduces spurious associations between disease progression and genetic variants that are truly only associated with disease incidence. Methods of statistical adjustment to reduce this bias have been published, but rely on assumptions regarding the genetic correlation of disease incidence and disease progression which are likely to be violated in many human diseases. MR-Horse is a recently published Bayesian method to estimate the parameters of a general model of genetic pleiotropy in the setting of Mendelian Randomisation. We adapted this method to provide bias-reduced GWAS estimates of associations with disease progression, robust to the genetic correlation of disease incidence and disease progression and robust to the presence of pleiotropic variants with effects on both incidence and progression. We applied this adapted method to simulated GWAS of disease incidence and progression with pleiotropic variants and varying degrees of genetic correlation. When significant genetic correlation was present, the MR-Horse method produced less biased estimates than unadjusted analyses or analyses adjusted using other existing methods. Type 1 error rates with the MR-Horse method were consistently below the nominal 5% level, at the expense of a modest reduction in power. We then applied this method to summary statistics from the CKDGen consortium GWAS of kidney function decline. MR-Horse attenuated the effects of variants with known likely biased effects in the CKDGen GWAS, whilst preserving effects at loci with likely true effects.
P21-Activated Kinase 2 as a Novel Target for Ventricular Tachyarrhythmias Associated with Cardiac Adrenergic Stress and Hypertrophy.
Ventricular arrhythmias associated with cardiac adrenergic stress and hypertrophy pose a significant clinical challenge. We explored ventricular anti-arrhythmic effects of P21-activated kinase 2 (Pak2), comparing in vivo and ex vivo cardiomyocyte-specific Pak2 knockout (Pak2cko) or overexpression (Pak2ctg) murine models, under conditions of acute adrenergic stress, and hypertrophy following chronic transverse aortic constriction (TAC). Pak2 was downregulated 5 weeks following the latter TAC challenge. Cellular physiological, optical action potential and Ca2+ transient, measurements, demonstrated increased incidences of triggered ventricular arrhythmias, and prolonged action potential durations (APD) and altered Ca2+ transients with increases in their beat-to beat variations, in Pak2cko hearts. Electron microscopic, proteomic, and molecular biological methods revealed a mitochondrial localization of stress-related proteins on proteomic and phosphoproteomic analyses, particularly in TAC stressed Pak2cko mice. They further yielded accompanying evidence for mitochondrial oxidative stress, increased reactive oxygen species (ROS) biosynthesis, reduced mitochondrial complexes I-V, diminished ATP synthesis and elevated NADPH oxidase 4 (NOX4) levels. Pak2 overexpression and the novel Pak2 activator JB2019A ameliorated these effects, enhanced cardiac function and decreased the frequencies of triggered ventricular arrhythmias. Pak2 activation thus protects against ventricular arrhythmia associated with cardiac stress and hypertrophy, through unique mechanisms offering potential novel therapeutic anti-arrhythmic targets.
p21-Activated Kinases Present a New Drug Target for Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM), primarily involving mutations in sarcomeric proteins, is the most common form of inherited heart disease and a leading cause of sudden death in young adults and athletes. HCM patients present with cardiac hypertrophy, fibrosis, and diastolic dysfunction often in a progressive manner. Despite significant progress made in understanding the molecular genetic basis of HCM, there remains a lack of effective and specific treatment for preventing disease progression in HCM. This article first provides an overview of recent progress in understanding the pathogenic basis of disease progression in HCM, in particular dysfunctional calcium handling, mitochondrial impairment, and endoplasmic reticulum stress. This article then analyses the evidence for critical roles of the multifunctional enzymes P21-activated kinase-1 and 2 (Pak1/2) in the heart and our opinion on their therapeutic value as a promising druggable target in pathological hypertrophy and associated ventricular arrhythmias.
Right Ventricular Strain Improves Cardiac MRI-based Prognostication in Heart Failure with Preserved Ejection Fraction.
Background Right ventricular (RV) function is an independent predictor of clinical status and prognosis in multiple cardiovascular diseases; however, the prognostic value of RV strain in patients with heart failure with preserved ejection fraction (HFpEF) remains largely unknown. Purpose To determine the associations between RV strain variables derived from cardiac MRI feature tracking and adverse outcomes in patients with HFpEF. Materials and Methods This retrospective study included patients with HFpEF who underwent cardiac MRI from January 2010 to December 2018. The primary end point was all-cause mortality. The results were validated in a cohort of patients with HFpEF enrolled from January 2019 to June 2021. Cox regression analysis was performed to assess the associations between variables and clinical outcomes. Results The development cohort comprised 1019 patients (mean age, 56.9 years ± 12.3 [SD]; 710 men), and the validation cohort comprised 273 patients (mean age, 55.3 years ± 14.0; 191 men). During a median follow-up of 7.8 and 3.9 years, respectively, 103 patients in the development cohort and nine in the validation cohort died. Multivariable Cox regression analysis showed that RV global longitudinal and circumferential strain were independent predictors of all-cause mortality (adjusted hazard ratio per 1% increase, 1.07 [95% CI: 1.02, 1.12; P = .005] and 1.13 [95% CI: 1.05, 1.21; P < .001], respectively). The full model based on clinical, conventional imaging, and RV strain variables demonstrated the best discrimination performance in the development (C index = 0.794) and validation (C index = 0.782) cohorts. In a subgroup with T1 mapping data, RV global longitudinal and circumferential strain remained independent predictors after separate adjustment for native T1 value and extracellular volume fraction (all models, P < .05). Conclusion RV global longitudinal and circumferential strain derived from cardiac MRI were independent predictors of adverse outcomes in patients with HFpEF, providing greater prognostic value than traditional clinical and imaging-derived risk markers. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Murphy and Quinn in this issue.