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Despite the identification of numerous genetic variants affecting SBP in European populations, their applicability in admixed populations remains unclear. This study evaluates the predictive efficacy of a systolic blood pressure (SBP) polygenic risk score (PRS), derived from the UK Biobank data, in two Brazilian cohorts. We analyzed 944 K genetic variants consistent across an independent UK Biobank dataset, Brazilian cohorts, and HapMap database. Results show a significant association between increased PRS and SBP, as well as hypertension, in each study groups analyzed. An increase of one standard deviation in the PRS showed a significant association with SBP (β [95% CI] (mmHg) = 5.2 [5.1-5.3], 2.8 [2.1-3.5] and 2.6 [2.2-3.0]) and hypertension (odds ratio (OR) [95% CI] = 1.56 [1.54-1.56], 1.28 [1.2-1.4] and 1.47 [1.3-1.6]) in an independent UKB dataset, Baependi, and Pelotas, respectively. The associations were weaker in the Brazilian samples and the reduced association was noticeable in the Pelotas vs. the UK comparison for hypertension stages 1 and 2 (OR [95% CI] = 2.1 [1.5-3.1] and 3.0 [1.9-4.7] vs. 2.5 [2.2-2.8] and 4.9 [4.4-5.6]), whereas the Baependi data showed no significance for stage 1 hypertension. This trend mirrors findings in homogeneous African and Asian populations with diverse genetic architecture, highlighting the limitations of European-based PRS also in admixed populations. These insights are crucial for developing tailored disease prevention and management strategies in ethnically diverse groups., Competing Interests: Declarations Competing interests The author(s) declare no competing interests. Ethics approval and consent to participate This study was approved by University of São Paulo Medical School ethical committee (CAAE number 37534720.0.0000.0068) and was conducted according to the guidelines of the Declaration of Helsinki. Written informed consent was obtained for all subjects involved in the study., (© 2024. The Author(s).)

Background: An improved understanding of the natural history in NYHA functional class I patients with obstructive hypertrophic cardiomyopathy (oHCM) is needed., Objectives: Using a multicenter registry (SHaRe [Sarcomeric Human Cardiomyopathy Registry]), this study described the natural history in patients with oHCM who were classified as NYHA functional class I at the initial visit compared with patients classified as NYHA functional class II and reported baseline characteristics associated with incident clinical events., Methods: Incident events assessed included a composite of NYHA functional class III to IV symptoms, left ventricular ejection fraction <50%, atrial fibrillation, stroke, ventricular arrhythmias, septal reduction therapy, ventricular assist device or transplantation, or death. Factors associated with incident events were determined using Kaplan-Meier, Cox proportional hazards, and restricted cubic spline models., Results: Of 7,964 patients with HCM in SHaRe, 1,239 patients with oHCM met inclusion criteria; 598 were in NYHA functional class I at the initial visit (age 48 ± 17 years; 31.1% female; peak gradient, 75 ± 40 mm Hg). At 5-year follow-up, the composite event rate of NYHA functional class I patients was 28% compared with 44% (P < 0.001) in 641 NYHA functional class II patients with oHCM (age 54 ± 16 years; 46.5% female; peak gradient, 83 ± 39 mm Hg). Left atrial (LA) diameter ≥45 mm (HR: 1.56 [95% CI: 1.14-2.12]; P = 0.005), female sex (HR: 1.61 [95% CI: 1.16-2.24]; P = 0.003), and older age (HR: 1.21 per 10 years [95% CI: 1.09-1.34]; P < 0.001), but not the magnitude of left ventricular outflow tract obstruction, were associated with a higher risk of the composite outcome in NYHA functional class I patients., Conclusions: Although NYHA functional class I patients with oHCM fared better than NYHA functional class II patients, more than one-fourth experienced adverse events over 5-year follow-up, especially if they were older, female, and/or had LA enlargement. Strategies to reduce the rate of clinical outcomes in NYHA functional class I patients warrant further study., Competing Interests: Funding Support and Author Disclosures Funding for SHaRe has been provided through an unrestricted research grant from Bristol Myers Squibb. Bristol Myers Squibb had no role in approving the content of this manuscript. This work was also supported by the Sir Jules Thorn Charitable Trust [21JTA], the Medical Research Council (UK), the British Heart Foundation [RE/18/4/34215], and the National Institutes of Health R Imperial College Biomedical Research Centre. For the purpose of open access, the authors have applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising. Dr Ahluwalia has received modest consulting income from Bristol Myers Squibb. Dr Olivotto has received research grants from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire Takeda, Menarini international, Chiesi, Boston Scientific; and has received consulting income from Bristol Myers Squibb, Cytokinetics, Amicus, Genzyme, Shire Takeda, Chiesi, Boston Scientific, Tenaya, Rocket Pharma, and Lexeo. Dr Owens has received consulting fees from Bristol Myers Squibb, Cytokinetics, Pfizer, Edgewise, Stealth, Lexeo, Lexicon, Tenaya, and BioMarin; and has received research funds from Bristol Myers Squibb. Dr Ware has received research support from Bristol Myers Squibb; and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics. Dr Ho has received consulting fees and unrestricted research funding from Bristol Myers Squibb (MyoKardia), Pfizer, Cytokinetics, BioMarin, Tenaya, Lexicon, and Viz.ai. Dr Lakdawala has received consulting income from Bristol Myers Squibb, Pfizer, Cytokinetics, Tenaya, and Akros; and has received research support from Bristol Myers Squibb and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Study Objectives: Sleep characteristics are associated with cardiovascular disease (CVD) risk and both sleep and CVD risk vary by gender. Our objective was to examine associations between polysomnographic sleep characteristics and CVD risk after excluding moderate-severe sleep apnea, and whether gender modifies these associations., Methods: This was a cross-sectional study with at-home polysomnography in adults in Brazil (n= 1,102 participants with apnea-hypopnea index (AHI)<15 events/hour). Primary exposures were N3, REM, wake after sleep onset (WASO), arousal index (AI) and AHI, and outcomes were blood pressure (BP) and lipid levels., Results: Associations between sleep and BP varied by gender. In women, more N3 was associated with lower systolic BP (-0.40 mmHg per 10 minutes, 95%CI -0.71, -0.09), lower diastolic BP (-0.29 mmHg per 10 minutes, 95%CI -0.50, -0.07), and lower odds of hypertension (OR 0.94, 95%CI 0.89, 0.98). In men, more WASO was associated with higher systolic BP (0.41 mmHg per 10 minutes, 95%CI 0.08, 0.74) and higher odds of hypertension (OR 1.07, 95%CI 1.01, 1.14). No interactions by gender were observed for lipids. More WASO was associated with lower total cholesterol (-0.71 per 10 minutes, 95%CI -1.37, -0.05). Higher AHI was associated with higher total cholesterol (+0.97 per event/hour, 95%CI 0.24, 1.70) and higher LDL (+0.84 per event/hour, 95%CI 0.04, 1.64)., Conclusions: N3 is more strongly associated with BP in women, which is consistent with other studies demonstrating gender differences in BP control and CVD risk and adds a novel risk factor. Longitudinal and interventional studies are required to determine whether changes in N3 result in BP changes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Importance: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have nephroprotective properties beyond those related to weight loss and glycemic control., Objective: To investigate the association of genetically proxied GLP-1RAs with kidney disease progression., Design, Setting, and Participants: This genetic association study assembled a national retrospective cohort of veterans aged 18 years or older from the US Department of Veterans Affairs Million Veteran Program between January 10, 2011, and December 31, 2021. Data were analyzed from November 2023 to February 2024., Exposures: Genetic risk score for systemic GLP1R gene expression that was calculated for each study participant based on genetic variants associated with GLP1R mRNA levels across all tissue samples within the Genotype-Tissue Expression project., Main Outcomes and Measures: The primary composite outcome was incident end-stage kidney disease or a 40% decline in estimated glomerular filtration rate. Cox proportional hazards regression survival analysis assessed the association between genetically proxied GLP-1RAs and kidney disease progression., Results: Among 353 153 individuals (92.5% men), median age was 66 years (IQR, 58.0-72.0 years) and median follow-up was 5.1 years (IQR, 3.1-7.2 years). Overall, 25.7% had diabetes, and 45.0% had obesity. A total of 4.6% experienced kidney disease progression. Overall, higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression in the unadjusted model (hazard ratio [HR], 0.96; 95% CI, 0.92-0.99; P = .02) and in the fully adjusted model accounting for baseline patient characteristics, body mass index, and the presence or absence of diabetes (HR, 0.96; 95% CI, 0.92-1.00; P = .04). The results were similar in sensitivity analyses stratified by diabetes or obesity status., Conclusions and Relevance: In this genetic association study, higher GLP1R gene expression was associated with a small reduction in risk of kidney disease progression. These findings support pleiotropic nephroprotective mechanisms of GLP-1RAs independent of their effects on body weight and glycemic control.

The mechanisms underlying racial inequities in uncontrolled hypertension have been limited to individual factors. We investigated racial inequities in uncontrolled hypertension and the explanatory role of economic segregation in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). All 3897 baseline participants with hypertension (2008-2010) were included. Uncontrolled hypertension (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg), self-reported race (White/Brown/Black people), and neighborhood economic segregation (low/medium/high) were analyzed cross-sectionally. We used decomposition analysis, which describes how much a disparity would change (disparity reduction; explained portion) and remain (disparity residual; unexplained portion) upon removing racial differences in economic segregation (i.e., if Black people had the distribution of segregation of White people, how much we would expect uncontrolled hypertension to decrease among Black people). Age- and gender-adjusted prevalence of uncontrolled hypertension (39.0%, 52.6%, and 54.2% for White, Brown, and Black participants, respectively) remained higher for Black and Brown vs White participants, regardless of economic segregation. Uncontrolled hypertension showed a dose-response pattern with increasing segregation levels for White but not for Black and Brown participants. After adjusting for age, gender, education, and study center, unexplained portion (disparity residual) of race on uncontrolled hypertension was 18.2% (95% CI 13.4%; 22.9%) for Black vs White participants and 12.6% (8.2%; 17.1%) for Brown vs White participants. However, explained portion (disparity reduction) through economic segregation was - 2.1% (- 5.1%; 1.3%) for Black vs White and 0.5% (- 1.7%; 2.8%) for Brown vs White participants. Although uncontrolled hypertension was greater for Black and Brown vs White people, racial inequities in uncontrolled hypertension were not explained by economic segregation., (© 2023. W. Montague Cobb-NMA Health Institute.)

Aim: Leg blood pressure (BP) measurement is needed when arm BP evaluation is not feasible, and calf BP, especially when measured in standing position, may have greater association with cardiovascular remodeling than arm BP. This study evaluated the relationship between calf and arm BP, and investigated whether calf BP would be superior to arm BP in predicting increased arterial stiffness [pulse wave velocity (PWV) > 10 m/s]., Methods: We evaluated clinical and laboratory characteristics, BP measurements, and PWV in 1397 individuals resident in Baependi, Brazil, between 2017 and 2019. Arm BP was measured in the seated and supine positions while calf BP was measured in supine and standing positions using digital oscillometric devices. Carotid-femoral PWV was measured using a noninvasive mechanotransducer., Results: The sample had 62.7% females, age = 48.1 ± 15.4 years and 8.4% with PWV >10 m/s. Results of linear regression analysis showed that BP values of 140/90 mmHg measured in the arm in supine and seated position were equivalent to calf supine BP values of 164/81 mmHg and 166/78 mmHg and calf standing BP values of 217/137 mmHg and 221/137 mmHg, respectively. Calf-arm BP differences were associated with age, glomerular filtration rate, body mass index, smoking, low-density lipoprotein-cholesterol, diabetes and height. Furthermore, stepwise logistic regression analysis revealed that arm supine systolic BP, but not calf BP measurements, was independently associated with increased arterial stiffness., Conclusion: Thresholds of ≈165/80 mmHg and ≈220/135 mmHg could be used for diagnosing hypertension when only calf measurements in supine and standing positions, respectively, are available. Conversely, calf BP was not superior to arm BP in predicting increased arterial stiffness., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Gender and age are well-established determinants of health and sleep health that influence overall health, which also often varies by gender and age. Sleep architecture is an important component of sleep health. The goal of this analysis was to examine whether associations between age and sleep stages differ by gender in the absence of moderate-severe obstructive sleep apnea (OSA) in a rural setting in Brazil. This study conducted polysomnography recordings in the Baependi Heart Study, a cohort of Brazilian adults. Our sample included 584 women and 309 men whose apnea-hypopnea index was ≤15 events/h. We used splines to distinguish non-linear associations between age, total sleep time, wake after sleep onset (WASO), N2, N3, and rapid-eye-movement sleep. The mean (standard deviation; range) age was 47 (14; 18-89) years. All sleep outcomes were associated with age. Compared to men, women had more N3 sleep and less WASO after adjusting for age. Model-based comparisons between genders at specific ages showed statistically higher mean WASO for men at ages 60 (+13.6 min) and 70 years (+19.5 min) and less N3 for men at ages 50 (-13.2 min), 60 (-19.0 min), and 70 years (-19.5 min) but no differences at 20, 30, 40 or 80 years. The other sleep measures did not differ by gender at any age. Thus, even in the absence of moderate-severe OSA, sleep architecture was associated with age across adulthood, and there were gender differences in WASO and N3 at older ages in this rural community., (© 2024 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Study Objectives: People with diabetes and prediabetes are more likely to have sleep-disordered breathing (SDB), but few studies examined sleep architecture in people with diabetes or prediabetes in the absence of moderate-severe SDB, which was the aim of our cross-sectional study., Methods: This cross-sectional sample is from the Baependi Heart Study, a family-based cohort of adults in Brazil. About 1074 participants underwent at-home polysomnography (PSG). Diabetes was defined as fasting glucose >125 mg/dL or HbA1c > 6.4 mmol/mol or taking diabetic medication, and prediabetes was defined as HbA1c ≥ 5.7 & <6.5 mmol/mol or fasting glucose ≥ 100 & ≤125 mg/dl. We excluded participants with an apnea-hypopnea index (AHI) ≥ 30 in primary analyses and ≥ 15 in secondary analysis. We compared sleep stages among the 3 diabetes groups (prediabetes, diabetes, neither)., Results: Compared to those without diabetes, we found shorter REM duration for participants with diabetes (-6.7 min, 95%CI -13.2, -0.1) and prediabetes (-5.9 min, 95%CI -10.5, -1.3), even after adjusting for age, gender, BMI, and AHI. Diabetes was also associated with lower total sleep time (-13.7 min, 95%CI -26.8, -0.6), longer slow-wave sleep (N3) duration (+7.6 min, 95%CI 0.6, 14.6) and higher N3 percentage (+2.4%, 95%CI 0.6, 4.2), compared to those without diabetes. Results were similar when restricting to AHI < 15., Conclusions: People with diabetes and prediabetes had less REM sleep than people without either condition. People with diabetes also had more N3 sleep. These results suggest that diabetes and prediabetes are associated with differences in sleep architecture, even in the absence of moderate-severe sleep apnea., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10 -8 ), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all., Competing Interests: Declaration of interests P.N. reports investigator-initiated research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. M.B.L. has received speaker and advisory fees from Otsuka, Reata, Bayer, and Sanofi Genzyme. G.P. has received speaker and advisory fees from Amgen, Bayer, Novartis, and Sanofi, and has received research grants from Bayer and Sanofi. L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted., Methods: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up., Results: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7 ., Conclusions: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM., Competing Interests: Disclosures The views expressed in this article are those of the authors, who declare that they have no conflict of interest, except for Dr Moon, who is the chief executive officer of Mycardium AI and has served on advisory boards for Genzyme and Sanofi.

Background: High blood pressure (BP) increases carotid intima-media thickness (CIMT). On the other hand, it is not clear whether the vascular abnormalities reflected in high CIMT may predict incident hypertension. The present study aims to investigate the association between CIMT and incident hypertension after 4 years of follow-up in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a multiethnic sample of middle-aged adults from six Brazilian cities., Methods: We analyzed data from 6682 ELSA-Brasil participants (aged 35-74) without hypertension and with complete CIMT data at baseline. After 4 years of follow-up, we describe hypertension incidence, stratifying the sample according to age, sex, and race-specific CIMT quartiles. We also built crude and adjusted Poisson regression models to analyze the association between mean and maximal CIMT values and incident hypertension., Results: We found incident hypertension in 987 (14.8%) participants. According to mean CIMT quartile groups, hypertension incidence varied from 10.2% (first quartile group) to 22.4% (fourth quartile group; P for trend <0.001). In fully adjusted models, 0.1 mm increments in mean CIMT values were associated with a 16% [relative risk (RR):1.16; 95% confidence interval (95% CI) 1.10-1.21; P  < 0.001] higher risk of incident hypertension, respectively. Results were similar when maximal CIMT values were considered instead of mean CIMT values., Conclusion: CIMT values at baseline strongly predicted incident hypertension after 4 years of follow-up in this large multiethnic cohort. This highlights the relationship between CIMT and BP and may provide important insights into the significance of this ultrasound measurement., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( ARSE and MMP16 ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease., Competing Interests: Bruce M. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Leslie S. Emery is now an employee of Celgene/Bristol Myers Squibb. Celgene/Bristol Myers Squibb had no role in the funding, design, conduct, or interpretation of this study. Nathan O. Stitziel has received research funding from Regeneron Pharmaceuticals, unrelated to this work. Karine A. Viaud-Martinez is an employee at Illumina Inc. Ryan W. Kim is an employee at Psomagen Inc. Roxona Mehran reports institutional research grants from Abbott Laboratories, Abiomed, Applied Therapeutics, AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich; consultant fees from Abbott Laboratories, Boston Scientific, CardiaWave, Chiesi, Janssen Scientific Affairs, Medscape/WebMD, Medtelligence (Janssen Scientific Affairs), Roivant Sciences, Sanofi, Siemens Medical Solutions; consultant fees paid to the institution from Abbott Laboratories, Bristol-Myers Squibb; advisory board, funding paid to the institution from Spectranetics/Philips/Volcano Corp; consultant (spouse) from Abiomed, The Medicines Company, Merck; Equity <1% from Claret Medical, Elixir Medical; DSMB Membership fees paid to the institution from Watermark Research Partners; consulting (no fee) from Idorsia Pharmaceuticals Ltd., Regeneron Pharmaceuticals; Associate Editor for ACC, AMA. Rajeev Malhotra is a consultant for MyoKardia (now owned by BMS), Epizon Pharma, Renovacor, and Third Pole, a co-founder of Patch and Angea Biotherapeutics, and has received research funding from Angea Biotherapeutics, Bayer Pharmaceuticals, and Amgen. Adrienne M. Stilp receives funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. Pradeep Natarajan reports grants from Amgen, Apple, Boston Scientific, AstraZeneca, Allelica, Novartis, and Genentech, consulting income from GV, Blackstone Life Sciences, Foresite Labs, Apple, AstraZeneca, Allelica, Novartis, HeartFlow, and Genentech, is a scientific advisor to Esperion Therapeutics, Preciseli, and TenSixteen Bio, is a scientific co-founder of TenSixteen Bio, and spousal employment at Vertex, all unrelated to the present work. Clint L. Miller received a research grant from AstraZeneca for an unrelated project. The remaining authors declare no competing interests.

Objective: Expressing the cardiovascular disease (CVD) risk in relation to peers may complement the estimation of absolute CVD risk. We aimed to determine 10-year CVD risk percentiles by sex and age in the Brazilian population and evaluate their association with estimated long-term atherosclerotic CVD (ASCVD) risk., Methods: A cross-sectional analysis of baseline data from the ELSA-Brasil study was conducted in individuals aged 40-74 years without prior ASCVD. Ten-year CVD risk and long-term ASCVD risk were estimated by the WHO risk score and the Multinational Cardiovascular Risk Consortium tool, respectively. Ten-year risk percentiles were determined by ranking the calculated risks within each sex and age group., Results: Ten-year CVD risk versus percentile plots were constructed for each sex and age group using data from 13,364 participants (55% females; median age, 52 [IQR, 46-59] years). Long-term ASCVD risk was calculated in 12,973 (97.1%) participants. Compared to individuals at the <25 th risk percentile, those at the ≥75 th percentile had a greater risk of being in the highest quartile of long-term risk (ORs [95% CIs] 6.57 [5.18-8.30] in females and 11.59 [8.42-15.96] in males) in regression models adjusted for age, race, education, and 10-year CVD risk. In both sexes, the association between risk percentile and long-term risk weakened after age 50. A tool for calculating 10-year CVD risk and the corresponding percentile is available at https://bit.ly/3CzPUi6., Conclusions: We established percentiles of predicted 10-year CVD risk by sex and age in the Brazilian population, which independently reflect the estimated long-term ASCVD risk in younger individuals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RDS received honoraria for consulting, speaker activities, and research from Abbott, Ache, Amgen, AstraZeneca, Biolab, EMS, Hypera, Libbs, Esperion, Kowa, Getz Pharma, Novo Nordisk, Novartis, Merck, PTC Therapeutics, Pfizer, and Sanofi. MSB received honoraria for consulting, speaker activities, and research from EMS, Novo Nordisk, Sanofi, Novartis, GE Healthcare, and Bayer. Other authors have no interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( p < 5 × 10 -8 ) and suggestive ( p < 1 × 10 -6 ) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose ( FOXP1, MBOAT4, SKP2, STIM1, STX4 ), brain ( BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A ), and liver ( BRI3, FOXP1 ) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects., Competing Interests: IN is now employed by Celgene. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. SA is employed by and holds equity in 23andMe, Inc. Authors BK, MW, and CGa were employed by Helmholtz Zentrum München. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 de las Fuentes, Schwander, Brown, Bentley, Winkler, Sung, Munroe, Miller, Aschard, Aslibekyan, Bartz, Bielak, Chai, Cheng, Dorajoo, Feitosa, Guo, Hartwig, Horimoto, Kolčić, Lim, Liu, Manning, Marten, Musani, Noordam, Padmanabhan, Rankinen, Richard, Ridker, Smith, Vojinovic, Zonderman, Alver, Boissel, Christensen, Freedman, Gao, Giulianini, Harris, He, Hsu, Kühnel, Laguzzi, Li, Lyytikäinen, Nolte, Poveda, Rauramaa, Riaz, Robino, Sofer, Takeuchi, Tayo, van der Most, Verweij, Ware, Weiss, Wen, Yanek, Zhan, Amin, Arking, Ballantyne, Boerwinkle, Brody, Broeckel, Campbell, Canouil, Chai, Ida Chen, Chen, Chitrala, Concas, de Faire, de Mutsert, de Silva, de Vries, Do, Faul, Fisher, Floyd, Forrester, Friedlander, Girotto, Gu, Hallmans, Heikkinen, Heng, Homuth, Hunt, Ikram, Jacobs, Kavousi, Khor, Kilpeläinen, Koh, Komulainen, Langefeld, Liang, Liu, Liu, Lohman, Mägi, Manichaikul, McKenzie, Meitinger, Milaneschi, Nauck, Nelson, O’Connell, Palmer, Pereira, Perls, Peters, Polašek, Raitakari, Rice, Rice, Rich, Sabanayagam, Schreiner, Shu, Sidney, Sims, Smith, Starr, Strauch, Tai, Taylor, Tsai, Uitterlinden, van Heemst, Waldenberger, Wang, Wei, Wilson, Xuan, Yao, Yu, Yuan, Zhao, Becker, Bonnefond, Bowden, Cooper, Deary, Divers, Esko, Franks, Froguel, Gieger, Jonas, Kato, Lakka, Leander, Lehtimäki, Magnusson, North, Ntalla, Penninx, Samani, Snieder, Spedicati, van der Harst, Völzke, Wagenknecht, Weir, Wojczynski, Wu, Zheng, Zhu, Bouchard, Chasman, Evans, Fox, Gudnason, Hayward, Horta, Kardia, Krieger, Mook-Kanamori, Peyser, Province, Psaty, Rudan, Sim, Smith, van Dam, van Duijn, Wong, Arnett, Rao, Gauderman, Liu, Morrison, Rotter and Fornage.)

Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression., Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM., Design, Setting, and Participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022., Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years)., Main Outcomes and Measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels)., Results: This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM., Conclusions and Relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression., Trial Registration: ClinicalTrials.gov Identifier: NCT01912534.

Elevated levels of glycoprotein acetylation (GlycA) and C-reactive protein (CRP) have been associated with carotid artery plaque (CAP). However, it is not yet established if elevations in both inflammatory biomarkers provide incremental association with CAP. This study aimed evaluate the cross-sectional association of high CRP and GlycA with CAP at baseline participants from the ELSA-Brasil adult cohort. Participants with information on CRP, GlycA, and CAP with neither previous cardiovascular disease nor CRP >10 mg/L were included. High GlycA and CRP were defined as values within upper quintile and >3 mg/L, respectively. Participants were classified into 4 groups: 1. nonelevated CRP/GlycA (reference group); 2. elevated CRP alone; 3. elevated GlycA alone; and 4. both elevated. The analysis included 4,126 participants with median age of 50 years-old, being 54.2% of women. Prevalence of CAP was 36.1%. Participants with high CRP had the highest frequency of obesity, whereas participants with high GlycA presented higher cardiovascular risk factor burden and were more likely to have CAP than the reference group (odds ratio [OR] 1.39, 95% confidence interval [CI] 1.11 to 1.73), persisting after multivariable adjustment (OR 1.37, 95% CI 1.02 to 1.83). Participants with both elevated CRP and GlycA were more likely to have CAP in crude (OR 1.35, 95% CI 1.10 to 1.65) but not in adjusted models. The findings suggest potential different biologic pathways between inflammation and carotid atherosclerosis: high GlycA was associated with CAP whereas high CRP was more associated with obesity., Competing Interests: Declaration of Competing Interest William R Tebar reports financial support was provided by the State of São Paulo Research Foundation. RDS has received honoraria related to consulting, research and/or speaker activities from Abbott, Ache, Amgen, Amryt, AstraZeneca, Biolab, Esperion, EMS, Getz Pharma, Kowa, Libbs, Novo-Nordisk, Novartis, Merck, Pfizer (New York, New York), PTC, and Sanofi. MSB has received honoraria related to consulting, research, and/or speaker activities from EMS, Novo-Nordisk, Sanofi, Novartis, and Bayer. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure., (© 2023. The Author(s).)

Background: Known genetic causes of congenital heart disease (CHD) explain <40% of CHD cases, and interpreting the clinical significance of variants with uncertain functional impact remains challenging. We aim to improve diagnostic classification of variants in patients with CHD by assessing the impact of noncanonical splice region variants on RNA splicing., Methods: We tested de novo variants from trio studies of 2649 CHD probands and their parents, as well as rare (allele frequency, <2×10 - 6 ) variants from 4472 CHD probands in the Pediatric Cardiac Genetics Consortium through a combined computational and in vitro approach., Results: We identified 53 de novo and 74 rare variants in CHD cases that alter splicing and thus are loss of function. Of these, 77 variants are in known dominant, recessive, and candidate CHD genes, including KMT2D and RBFOX2 . In 1 case, we confirmed the variant's predicted impact on RNA splicing in RNA transcripts from the proband's cardiac tissue. Two probands were found to have 2 loss-of-function variants for recessive CHD genes HECTD1 and DYNC2H1 . In addition, SpliceAI-a predictive algorithm for altered RNA splicing-has a positive predictive value of ≈93% in our cohort., Conclusions: Through assessment of RNA splicing, we identified a new loss-of-function variant within a CHD gene in 78 probands, of whom 69 (1.5%; n=4472) did not have a previously established genetic explanation for CHD. Identification of splice-altering variants improves diagnostic classification and genetic diagnoses for CHD., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01196182., Competing Interests: Disclosures None.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A)., (© 2023. The Author(s).)

Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi) and, among all the chronic manifestations of the disease, Chronic Chagas Cardiomyopathy (CCC) is the most severe outcome. Despite high burden and public health importance in Latin America, there is a gap in understanding the molecular mechanisms that results in CCC development. Previous studies showed that T. cruzi uses the host machinery for infection and replication, including the repurposing of the responses to intracellular infection such as mitochondrial activity, vacuolar membrane, and lysosomal activation in benefit of parasite infection and replication. One common signaling upstream to many responses to parasite infection is mTOR pathway, previous associated to several downstream cellular mechanisms including autophagy, mitophagy and lysosomal activation. Here, using human iPSC derived cardiomyocytes (hiPSCCM), we show the mTOR pathway is activated in hiPSCCM after T. cruzi infection, and the inhibition of mTOR with rapamycin reduced number of T. cruzi 48 h post infection (hpi). Rapamycin treatment also reduced lysosome migration from nuclei region to cell periphery resulting in less T. cruzi inside the parasitophorous vacuole (PV) in the first hour of infection. In addition, the number of parasites leaving the PV to the cytoplasm to replicate in later times of infection was also lower after rapamycin treatment. Altogether, our data suggest that host's mTOR activation concomitant with parasite infection modulates lysosome migration and that T. cruzi uses this mechanism to achieve infection and replication. Modulating this mechanism with rapamycin impaired the success of T. cruzi life cycle independent of mitophagy., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Hypertrophic cardiomyopathy is one of the most common inherited cardiomyopathies and a leading cause of sudden cardiac death in young adults. Despite profound insights into the genetics, there is imperfect correlation between mutation and clinical prognosis, suggesting complex molecular cascades driving pathogenesis. To investigate this, we performed an integrated quantitative multi-omics (proteomic, phosphoproteomic, and metabolomic) analysis to illuminate the early and direct consequences of mutations in myosin heavy chain in engineered human induced pluripotent stem-cell-derived cardiomyocytes relative to late-stage disease using patient myectomies. We captured hundreds of differential features, which map to distinct molecular mechanisms modulating mitochondrial homeostasis at the earliest stages of pathobiology, as well as stage-specific metabolic and excitation-coupling maladaptation. Collectively, this study fills in gaps from previous studies by expanding knowledge of the initial responses to mutations that protect cells against the early stress prior to contractile dysfunction and overt disease.

Introduction: Chagas cardiomyopathy, a disease caused by Trypanosoma cruzi ( T. cruzi ) infection, is a major contributor to heart failure in Latin America. There are significant gaps in our understanding of the mechanism for infection of human cardiomyocytes, the pathways activated during the acute phase of the disease, and the molecular changes that lead to the progression of cardiomyopathy., Methods: To investigate the effects of T. cruzi on human cardiomyocytes during infection, we infected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) with the parasite and analyzed cellular, molecular, and metabolic responses at 3 hours, 24 hours, and 48 hours post infection (hpi) using transcriptomics (RNAseq), proteomics (LC-MS), and metabolomics (GC-MS and Seahorse) analyses., Results: Analyses of multiomic data revealed that cardiomyocyte infection caused a rapid increase in genes and proteins related to activation innate and adaptive immune systems and pathways, including alpha and gamma interferons, HIF-1α signaling, and glycolysis. These responses resemble prototypic responses observed in pathogen-activated immune cells. Infection also caused an activation of glycolysis that was dependent on HIF-1α signaling. Using gene editing and pharmacological inhibitors, we found that T. cruzi uptake was mediated in part by the glucose-facilitated transporter GLUT4 and that the attenuation of glycolysis, HIF-1α activation, or GLUT4 expression decreased T. cruzi infection. In contrast, pre-activation of pro-inflammatory immune responses with LPS resulted in increased infection rates., Conclusion: These findings suggest that T. cruzi exploits a HIF-1α-dependent, cardiomyocyte-intrinsic stress-response activation of glycolysis to promote intracellular infection and replication. These chronic immuno-metabolic responses by cardiomyocytes promote dysfunction, cell death, and the emergence of cardiomyopathy., Competing Interests: DB is co-founder of LizarBio Therapeutics. CT works as consultant for Myokardia Inc. JS and CS are founders of Myokardia (a Bristol Myers Squibb Subsidiary) and consultants for Maze and BridgeBio. CS serves on the Board of Directors for Merck Pharmaceuticals and the Burroughs Wellcome Fund. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Venturini, Alvim, Padilha, Toepfer, Gorham, Wasson, Biagi, Schenkman, Carvalho, Salgueiro, Cardozo, Krieger, Pereira, Seidman and Seidman.)

Background and Aims: Familial hypercholesterolemia (FH) variants are associated with higher atherosclerotic cardiovascular disease risk (ASCVD) even when compared with other forms of severe hypercholesterolemia, especially in young people. Lipid lowering therapies (LLT) may change hypercholesterolemia natural history. This study aimed at evaluating factors associated with occurrence of ASCVD in old severe hypercholesterolemics diagnosed or not with FH and undergoing LLT., Methods: Hypercholesterolemic individuals ≥60 years participating on a genetic cascade screening for FH were divided in 4 groups (2 × 2) according to the presence (variant+) or not (variant-) of FH genetic variants and previous ASCVD (ASCVD+ and ASCVD-). Biomarkers associated with new incident ASCVD events were tested using Cox models. Continuous data shown as medians (%25; %75)., Results: From 4,111 genotyped individuals, 377 (9.1%) were elderly [age 66 (63; 71) years], 28.9% males, 42.7% variant+, 32.1% with previous ASCVD, LLT duration 9 (5; 16) years, and on treatment LDL-cholesterol 144 (109; 200) mg/dL. After 4.8 (7; 3) years of follow up there were 47 incident events (12.4%, 2.7% patient/year). The annualized event rates were 0.8% (95% CI 0.36%; 1.70%), 2.3% (95% CI 1.3%; 4.1%), 5.2% (95% CI 2.8%; 9.7%) and 6.3% (95% CI 4.0%; 10.0%) respectively for groups variant-/ASCVD-, variant+/ASCVD-, variant-/ASCVD+ and, variant+/ASCVD+ (p log rank p < 0.001). Only presence of previous ASCVD was independently associated with incident ASCVD [hazard ratio 3.236 (95%CI 1.497-6.993, p = 0.003)]. No interaction was found for previous ASCVD and variants., Conclusions: In old severe hypercholesterolemic individuals undergoing long-term LLT previous ASCVD was associated with incident events while FH causing variants were not., Competing Interests: Declaration of competing interest ERC has received honoraria related to speaker activities from Amgen, Ache and Novartis; MHM has received honoraria related to speaker activities from Amgen; VZR has received honoraria related to speaker activities from: Ache, Amgen, Novo-Nordisk and Sanofi; MSB has received honoraria from Boston Scientific and Novo-Nordisk; RDS has received honoraria related to consulting, research and/or speaker activities from: Abbott, Ache, Amgen, Amryt, Astra Zeneca, Biolab, Esperion, Getz Pharma, Kowa, Libbs, Novo-Nordisk, Novartis, Merck, Pfizer, PTC Therapeutics and Sanofi; all other authors have none to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Chronic Chagas Cardiomyopathy (CCC) usually develops between 10 and 20 years after the first parasitic infection and is one of the leading causes of end-stage heart failure in Latin America. Despite the great inter-individual variability in CCC susceptibility (only 30% of infected individuals ever present CCC), there are no known predictors for disease development in those chronically infected., Methodology/principal Findings: We describe a new susceptibility locus for CCC through a GWAS analysis in the SaMi-Trop cohort, a population-based study conducted in a Chagas endemic region from Brazil. This locus was also associated with CCC in the REDS II Study. The newly identified locus (rs34238187, OR 0.73, p-value 2.03 x 10-9) spans a haplotype of approximately 30Kb on chromosome 18 (chr18: 5028302-5057621) and is also associated with 80 different traits, most of them blood protein traits significantly enriched for immune-related biological pathways. Hi-C data show that the newly associated locus is able to interact with chromatin sites as far as 10Mb on chromosome 18 in a number of different cell types and tissues. Finally, we were able to confirm, at the tissue transcriptional level, the immune-associated blood protein signature using a multi-tissue differential gene expression and enrichment analysis., Conclusions/significance: We suggest that the newly identified locus impacts CCC risk among T cruzi infected individuals through the modulation of a downstream transcriptional and protein signature associated with host-parasite immune response. Functional characterization of the novel risk locus is warranted., Competing Interests: The authors have declared that no competing interests exist.

Chagas disease is a parasitic disease from South America, affecting around 7 million people worldwide. Decades after the infection, 30% of people develop chronic forms, including Chronic Chagas Cardiomyopathy (CCC), for which no treatment exists. Two stages characterized this form: the moderate form, characterized by a heart ejection fraction (EF) ≥ 0.4, and the severe form, associated to an EF < 0.4. We propose two sets of DNA methylation biomarkers which can predict in blood CCC occurrence, and CCC stage. This analysis, based on machine learning algorithms, makes predictions with more than 95% accuracy in a test cohort. Beyond their predictive capacity, these CpGs are located near genes involved in the immune response, the nervous system, ion transport or ATP synthesis, pathways known to be deregulated in CCCs. Among these genes, some are also differentially expressed in heart tissues. Interestingly, the CpGs of interest are tagged to genes mainly involved in nervous and ionic processes. Given the close link between methylation and gene expression, these lists of CpGs promise to be not only good biomarkers, but also good indicators of key elements in the development of this pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brochet, Ianni, Nunes, Frade, Teixeira, Mady, Ferreira, Kuramoto, Pissetti, Saba, Cândido, Dias, Sampaio, Marin-Neto, Fragata, Zaniratto, Siqueira, Peixoto, Rigaud, Buck, Almeida, Lin-Wang, Schmidt, Martinelli, Hirata, Donadi, Rodrigues Junior, Pereira, Kalil, Spinelli, Cunha-Neto and Chevillard.)

Premature atrial contractions (PACs) are frequently observed on electrocardiograms and are associated with increased risks of atrial fibrillation (AF), stroke, and mortality. In this study, we aimed to identify genetic susceptibility loci for PAC frequency. We performed a genome-wide association study meta-analysis with PAC frequency obtained from ambulatory cardiac monitoring in 4,831 individuals of European ancestry. We identified a genome-wide significant locus at the SCN5A gene. The lead variant, rs7373862, located in an intron of SCN5A , was associated with an increase of 0.12 [95% CI 0.08-0.16] standard deviations of the normalized PAC frequency per risk allele. Among genetic variants previously associated with AF, there was a significant enrichment in concordance of effect for PAC frequency (n = 73/106, p = 5.1 × 10 -5 ). However, several AF risk loci, including PITX2 , were not associated with PAC frequency. These findings suggest the existence of both shared and distinct genetic mechanisms for PAC frequency and AF., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Background: The association between ideal cardiovascular health (ICVH) status and atrial fibrillation or flutter (AFF) diagnosis has been less studied compared to other cardiovascular diseases., Objective: To analyze the association between AFF diagnosis and ICVH metrics and scores in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)., Methods: This study analyzed data from 13,141 participants with complete data. Electrocardiographic tracings were coded according to the Minnesota Coding System, in a centralized reading center. ICVH metrics (diet, physical activity, body mass index, smoking, blood pressure, fasting plasma glucose, and total cholesterol) and scores were calculated as proposed by the American Heart Association. Crude and adjusted binary logistic regression models were built to analyze the association of ICVH metrics and scores with AFF diagnosis. Significance level was set at 0.05., Results: The sample had a median age of 55 years and 54.4% were women. In adjusted models, ICVH scores were not significantly associated with prevalent AFF diagnosis (odds ratio [OR]:0.96; 95% confidence interval [95% CI]:0.80-1.16; p=0.70). Ideal blood pressure (OR:0.33; 95% CI:0.15-0.74; p=0.007) and total cholesterol (OR:1.88; 95% CI:1.19-2.98; p=0.007) profiles were significantly associated with AFF diagnosis., Conclusions: No significant associations were identified between global ICVH scores and AFF diagnosis after multivariable adjustment in our analyses, at least partially due to the antagonistic associations of AFF with blood pressure and total cholesterol ICVH metrics. Our results suggest that estimating the prevention of AFF burden using global ICVH scores may not be adequate, and ICVH metrics should be considered in separate.

The coronavirus disease 2019 (COVID-19) pandemic has changed the paradigms for disease surveillance and rapid deployment of scientific-based evidence for understanding disease biology, susceptibility and treatment. We have organized a large-scale genome-wide association study (GWAS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals in Sao Paulo, Brazil, one of the most affected areas of the pandemic in the country, itself one of the most affected in the world. Here, we present the results of the initial analysis in the first 5233 participants of the BRACOVID study. We have conducted a GWAS for COVID-19 hospitalization enrolling 3533 cases (hospitalized COVID-19 participants) and 1700 controls (non-hospitalized COVID-19 participants). Models were adjusted by age, sex and the 4 first principal components. A meta-analysis was also conducted merging BRACOVID hospitalization data with the Human Genetic Initiative (HGI) Consortia results. BRACOVID results validated most loci previously identified in the HGI meta-analysis. In addition, no significant heterogeneity according to ancestral group within the Brazilian population was observed for the two most important COVID-19 severity associated loci: 3p21.31 and Chr21 near IFNAR2. Using only data provided by BRACOVID, a new genome-wide significant locus was identified on Chr1 near the genes DSTYK and RBBP5. The associated haplotype has also been previously associated with a number of blood cell related traits and might play a role in modulating the immune response in COVID-19 cases., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Competing Interests: Conflict of interest: none declared.

Aims: To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events., Methods and Results: Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12-4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75-9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16-26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20-49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98-2.91, P = 0.0600)., Conclusions: Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Chagas disease is a tropical zoonosis caused by Trypanosoma cruzi . After infection, the host present an acute phase, usually asymptomatic, in which an extensive parasite proliferation and intense innate immune activity occurs, followed by a chronic phase, characterized by low parasitemia and development of specific immunity. Most individuals in the chronic phase remain without symptoms or organ damage, a state called indeterminate IND form. However, 20 to 40% of individuals develop cardiac or gastrointestinal complications at any time in life. Cardiomyocytes have an important role in the development of Chronic Chagas Cardiomyopathy (CCC) due to transcriptional and metabolic alterations that are crucial for the parasite survival and replication. However, it still not clear why some infected individuals progress to a cardiomyopathy phase, while others remain asymptomatic. In this work, we used hiPSCs-derived cardiomyocytes (hiPSC-CM) to investigate patterns of infection, proliferation and transcriptional response in IND and CCC patients. Our data show that T. cruzi infection and proliferation efficiency do not differ significantly in PBMCs and hiPSC-CM from both groups. However, RNA-seq analysis in hiPSC-CM infected for 24 hours showed a significantly different transcriptional response to the parasite in cells from IND or CCC patients. Cardiomyocytes from IND showed significant differences in the expression of genes related to antigen processing and presentation, as well as, immune co-stimulatory molecules. Furthermore, the downregulation of collagen production genes and extracellular matrix components was significantly different in these cells. Cardiomyocytes from CCC, in turn, showed increased expression of mTORC1 pathway and unfolded protein response genes, both associated to increased intracellular ROS production. These data point to a differential pattern of response, determined by baseline genetic differences between groups, which may have an impact on the development of a chronic outcome with or without the presentation of cardiac symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oliveira, Venturini, Alvim, Feijó, Dinardo, Sabino, Seidman, Seidman, Krieger and Pereira.)

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of LDL-C leading to premature cardiovascular disease (CAD). Only about 40% of individuals with a clinical diagnosis of FH have a causative genetic variant identified, and a proportion of genetically negative cases may have a polygenic cause rather than a still unidentified monogenic cause. This work aims to evaluate and validate the role of a polygenic risk score (PRS) associated with hypercholesterolemia in a Brazilian FH cohort and its clinical implications., Methods: We analyzed a previously derived PRS of 12 and 6 SNPs (Single Nucleotide Polymorphism) in 684 FH individuals (491 mutation-negative [FH/M-], 193 mutation-positive [FH/M+]) and in 1605 controls. Coronary artery calcium (CAC) score was also evaluated., Results: The PRS was independently associated with LDL-C in control individuals ( p  < 0.001). Within this group, in individuals in the highest quartile of the 12 SNPs PRS, the odds ratio for CAC score >100 was 1.7 (95% CI: 1.01-2.88, p  = 0.04) after adjustment for age and sex. Subjects in the FH/M- group had the highest mean score in both 12 and 6 SNPs PRS (38.25 and 27.82, respectively) when compared to the other two groups ( p  = 2.2 × 10-16). Both scores were also higher in the FH/M+ group (36.48 and 26.26, respectively) when compared to the control group (p < 0.001 for the two scores) but inferior to the FH/M- group. Within FH individuals, the presence of a higher PRS score was not associated with LDL-C levels or with CAD risk., Conclusion: A higher PRS is associated with significantly higher levels of LDL-C and it is independently associated with higher CAC in the Brazilian general population. A polygenic cause can explain a fraction of FH/M- individuals but does not appear to be a modulator of the clinical phenotype among FH individuals, regardless of mutation status., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RDS has received honoraria related to consulting, research and or speaker activities from: Abbott, Amgen, Aché, Astra Zeneca, Esperion, EMS, GETZ Pharma, Kowa, Libbs, Merck, MSD, Novo-Nordisk, Novartis, PTC Therapeutics, Pfizer, Roche and Sanofi. IRL has received a scholarship from Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (CAPES) #88887.531079/2020-00. RDS is recipient of a scholarship from Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico, Brazil (CNPq) #303734/2018-3. The ELSA-Brasil baseline study was supported by the 10.13039/501100006506Brazilian Ministry of Health (Science and Technology Department) and the BrazilianMinistry of Science and Technology (10.13039/501100004809Financiadora de Estudos e Projetos and 10.13039/501100003593CNPq 10.13039/100013101National Research Council)., (© 2022 The Authors.)

Background: Truncating variants in the desmosomal gene PKP2 (PKP2 tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity., Methods: We identified individuals with PKP2 tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The PKP2 tv minor allelic frequency in the UKB was compared with a second cohort of probands with a clinical diagnosis of ARVC (ARVC cohort), with a figure of 1:5000 assumed for disease prevalence. In silico predictors of variant pathogenicity (combined annotation-dependent depletion and Splice AI [Illumina, Inc.]) were assessed., Results: PKP2 tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique PKP2 tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with PKP2 tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10 -4 ). The ARVC cohort included 487 ARVC probands with 144 distinct PKP2 tv, with 25 PKP2 tv common to both cohorts. The odds ratio for ARVC for the 25 common PKP2 tv was 0.047 (95% CI, 0.001-0.268; P= 2.43×10 -6 ), and only favored ARVC (odds ratio >1) for a single variant, p.Arg79*. In silico variant analysis did not differentiate PKP2 tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with PKP2 tv (7.9% versus 4.3%; odds ratio, 2.11; P =0.005)., Conclusions: PKP2 tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how PKP2 tv cause ARVC in combination with associated genetic and environmental risk factors.

Background: Heart transplantation provides a significant improvement in survival and quality of life for patients with end-stage heart disease, however many recipients experience different levels of graft rejection that can be associated with significant morbidities and mortality. Current clinical standard-of-care for the evaluation of heart transplant acute rejection (AR) consists of routine endomyocardial biopsy (EMB) followed by visual assessment by histopathology for immune infiltration and cardiomyocyte damage. We assessed whether the sensitivity and/or specificity of this process could be improved upon by adding RNA sequencing (RNA-seq) of EMBs coupled with histopathological interpretation., Methods: Up to 6 standard-of-care, or for-cause EMBs, were collected from 26 heart transplant recipients from the prospective observational Clinical Trials of Transplantation (CTOT)-03 study, during the first 12-months post-transplant and subjected to RNA-seq (n = 125 EMBs total). Differential expression and random-forest-based machine learning were applied to develop signatures for classification and prognostication., Results: Leveraging the unique longitudinal nature of this study, we show that transcriptional hallmarks for significant rejection events occur months before the actual event and are not visible using traditional histopathology. Using this information, we identified a prognostic signature for 0R/1R biopsies that with 90% accuracy can predict whether the next biopsy will be 2R/3R., Conclusions: RNA-seq-based molecular characterization of EMBs shows significant promise for the early detection of cardiac allograft rejection., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Competing Interests: None declared.

Microtia is a congenital malformation that encompasses mild hypoplasia to complete loss of the external ear, or pinna. Although the contribution of genetic variation and environmental factors to microtia remains elusive, Amerindigenous populations have the highest reported incidence. Here, using both transmission disequilibrium tests and association studies in microtia trios (parents and affected child) and microtia cohorts enrolled in Latin America, we map an ∼10-kb microtia locus (odds ratio = 4.7; P = 6.78e-18) to the intergenic region between Roundabout 1 (ROBO1) and Roundabout 2 (ROBO2) (chr3: 78546526 to 78555137). While alleles at the microtia locus significantly increase the risk of microtia, their penetrance is low (<1%). We demonstrate that the microtia locus contains a polymorphic complex repeat element that is expanded in affected individuals. The locus is located near a chromatin loop region that regulates ROBO1 and ROBO2 expression in induced pluripotent stem cell–derived neural crest cells. Furthermore, we use single nuclear RNA sequencing to demonstrate ROBO1 and ROBO2 expression in both fibroblasts and chondrocytes of the mature human pinna. Because the microtia allele is enriched in Amerindigenous populations and is shared by some East Asian subjects with craniofacial malformations, we propose that both populations share a mutation that arose in a common ancestor prior to the ancient migration of Eurasian populations into the Americas and that the high incidence of microtia among Amerindigenous populations reflects the population bottleneck that occurred during the migration out of Eurasia.

Objectives: This analysis describes the protocol of a study with a case-cohort to design to prospectively evaluate the incidence of subclinical atherosclerosis and Cardiovascular Disease (CVD) in Chronic Inflammatory Disease (CID) participants compared to non-diseased ones., Methods: A high-risk group for CID was defined based on data collected in all visits on self-reported medical diagnosis, use of medicines, and levels of high-sensitivity C-Reactive Protein >10 mg/L. The comparison group is the Aleatory Cohort Sample (ACS): a group with 10% of participants selected at baseline who represent the entire cohort. In both groups, specific biomarkers for DIC, markers of subclinical atherosclerosis, and CVD morbimortality will be tested using weighted Cox., Results: The high-risk group (n = 2,949; aged 53.6 ± 9.2; 65.5% women) and the ACS (n=1543; 52.2±8.8; 54.1% women) were identified. Beyond being older and mostly women, participants in the high-risk group present low average income (29.1% vs. 24.8%, p < 0.0001), higher BMI (Kg/m 2 ) (28.1 vs. 26.9, p < 0.0001), higher waist circumference (cm) (93.3 vs. 91, p < 0.0001), higher frequencies of hypertension (40.2% vs. 34.5%, p < 0.0001), diabetes (20.7% vs. 17%, p = 0.003) depression (5.8% vs. 3.9%, p = 0.007) and higher levels of GlycA a new inflammatory marker (p < 0.0001) compared to the ACS., Conclusions: The high-risk group selected mostly women, older, lower-income/education, higher BMI, waist circumference, and of hypertension, diabetes, depression, and higher levels of GlycA when compared to the ACS. The strategy chosen to define the high-risk group seems adequate given that multiple sociodemographic and clinical characteristics are compatible with CID., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Congenital heart disease (CHD) is the most common anomaly at birth, with a prevalence of ≈1%. While infants born to mothers with diabetes or obesity have a 2- to 3-fold increased incidence of CHD, the cause of the increase is unknown. Damaging de novo variants (DNV) in coding regions are more common among patients with CHD, but genome-wide rates of coding and noncoding DNVs associated with these prenatal exposures have not been studied in patients with CHD., Methods: DNV frequencies were determined for 1812 patients with CHD who had whole-genome sequencing and prenatal history data available from the Pediatric Cardiac Genomics Consortium's CHD GENES study (Genetic Network). The frequency of DNVs was compared between subgroups using t test or linear model., Results: Among 1812 patients with CHD, the number of DNVs per patient was higher with maternal diabetes (76.5 versus 72.1, t test P =3.03×10 -11 ), but the difference was no longer significant after including parental ages in a linear model (paternal and maternal correction P =0.42). No interaction was observed between diabetes risk and parental age (paternal and maternal interaction P =0.80 and 0.68, respectively). No difference was seen in DNV count per patient based on maternal obesity (72.0 versus 72.2 for maternal body mass index <25 versus maternal body mass index >30, t test P =0.86)., Conclusions: After accounting for parental age, the offspring of diabetic or obese mothers have no increase in DNVs compared with other children with CHD. These results emphasize the role for other mechanisms in the cause of CHD associated with these prenatal exposures., Registration: URL: https://clinicaltrials.gov; NCT01196182.

Objectives: Prior studies have examined sleep during the coronavirus disease 2019 (COVID-19) pandemic, but have few compared sleep measured both during and prior to COVID. We examined the impact of the COVID-19 pandemic on subjective sleep quality in general and separately by gender and age (<50 vs. ≥50 years). Further, we compared sleep quality between those who did and did not follow quarantine orders., Methods: This sample is from the Baependi Heart Study, a family-based cohort of adults in South-eastern Brazil. Longitudinal data were from 417 individuals who completed the Pittsburgh Sleep Quality Index (PSQI) twice: between January 2010 and September 2014 (pre-COVID) and during the COVID-19 stay-at-home order March-June, 2020. Cross-sectional analysis included 800 participants., Results: Mean (±SD) PSQI scores were significantly higher during than before COVID-19 (5.7 ± 3.8 vs. 5.0 ± 3.3, p < .01). This increase was significant among women and among adults ≥50 years but not in men or younger adults. The significant increase in PSQI was only observed in those who quarantined during COVID-19 (5.9 ±3.7 vs. 5.2 ±3.4, p < .01) and not those who did not quarantine (5.0 ± 3.7 vs. 4.5 ± 3, p = .12). In cross-sectional analyses, individuals who quarantined had higher PSQI scores than nonquarantined individuals (6.1 ± 3.9 vs. 5.0 ± 3.5, p < .01). The quarantine status-dependent differences were significant for women (6.4 ± 4 vs. 5.2 ± 3.7, p < .01) and older adults (6.6 ± 0.1 vs. 5.5 ± 3.3, p = .04). Differences by quarantine status were attenuated after adjusting for age and gender., Conclusions: Subjective sleep quality declined during the COVID-19 pandemic, particularly among women, older adults, and those compliant to quarantine orders., (Copyright © 2021 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification., Competing Interests: S.M.G. and A.M.S. receive funding from Seven Bridges Genomics to develop tools for the NHLBI BioData Catalyst consortium. All others authors declare no competing interests., (© 2022 The Author(s).)

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by the presence of high levels of total and low-density lipoprotein cholesterol (LDL-C). Statin treatment is recommended for all adults with FH., Objective: Here we have studied the main predictors of the use of lipid-lowering agents at one-year follow-up in a large cohort of FH patients., Methods: Open prospective cohort of individuals resident in São Paulo, Brazil who were enrolled in a FH cascade screening program. We used a multivariate logistic regression analysis to determine predictive variables for the non-adherence of lipid-lowering drugs., Results: A total of 1,360 HF participants were included. At the one-year follow-up (T1), the rates of lipid-lowering treatment were 92%, 76%, and 78% from the genetic positive proband (index cases, IC), genetic negative IC and genetic positive first-degree relatives, respectively. Receiving a positive genetic test for FH (OR: 4.85; CI 95%: 2.97 - 7.93, p value < 0.05), use of lipid-lowering treatment at T0 (OR: 5.01; CI 95%: 3.18 - 7.90, p value < 0.05) and age (OR: 1.04; CI 95%: 1.02 - 1.06) were independently associated with the use of a lipid-lowering drug at T1., Conclusion: Index cases with a positive genetic result increase their prevalence of lipid-lowering medication use. Positive relatives did not have the expected adherence; we could notice a significant increase in the prevalence of treatment starting after a positive genetic test. The independent predictors for lipid-lowering treatment were age, a positive genetic test and previous institution of treatment before the genetic test result., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

BackgroundThere is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.MethodsWe combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.ResultsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.ConclusionsThe major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P joint  < 5 × 10 -8 ), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P int  < 5 × 10 -8 ). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P int  = 2 × 10 -6 ). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P int  < 10 -3 ). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry., Methods and Results: We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89-2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76-6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28-0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74-1.97])., Conclusion: Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)