Genetic determinants of blood pressure and heart rate identified through ENU-induced mutagenesis with automated meiotic mapping.

We used N-ethyl-N-nitrosurea-induced germline mutagenesis combined with automated meiotic mapping to identify specific systolic blood pressure (SBP) and heart rate (HR) determinant loci. We analyzed 43,627 third-generation (G3) mice from 841 pedigrees to assess the effects of 45,378 variant alleles within 15,760 genes, in both heterozygous and homozygous states. We comprehensively tested 23% of all protein-encoding autosomal genes and found 87 SBP and 144 HR (with 7 affecting both) candidates exhibiting detectable hypomorphic characteristics. Unexpectedly, only 18 of the 87 SBP genes were previously known, while 26 of the 144 genes linked to HR were previously identified. Furthermore, we confirmed the influence of two genes on SBP regulation and three genes on HR control through reverse genetics. This underscores the importance of our research in uncovering genes associated with these critical cardiovascular risk factors and illustrate the effectiveness of germline mutagenesis for defining key determinants of polygenic phenotypes that must be studied in an intact organism.

Genome-wide study investigating effector genes and polygenic prediction for kidney function in persons with ancestry from Africa and the Americas.

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.

Enhancing Arrhythmogenic Right Ventricular Cardiomyopathy Detection and Risk Stratification: Insights from Advanced Echocardiographic Techniques.

INTRODUCTION: The echocardiographic diagnosis criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) are highly specific but sensitivity is low, especially in the early stages of the disease. The role of echocardiographic strain in ARVC has not been fully elucidated, although prior studies suggest that it can improve the detection of subtle functional abnormalities. The purposes of the study were to determine whether these advanced measures of right ventricular (RV) dysfunction on echocardiogram, including RV strain, increase diagnostic value for ARVC disease detection and to evaluate the association of echocardiographic parameters with arrhythmic outcomes. METHODS: The study included 28 patients from the Heart Institute of São Paulo ARVC cohort with a definite diagnosis of ARVC established according to the 2010 Task Force Criteria. All patients were submitted to ECHO's advanced techniques including RV strain, and the parameters were compared to prior conventional visual ECHO and CMR. RESULTS: In total, 28 patients were enrolled in order to perform ECHO's advanced techniques. A total of 2/28 (7%) patients died due to a cardiovascular cause, 2/28 (7%) underwent heart transplantation, and 14/28 (50%) patients developed sustained ventricular arrhythmic events. Among ECHO's parameters, RV dilatation, measured by RVDd (p = 0.018) and RVOT PSAX (p = 0.044), was significantly associated with arrhythmic outcomes. RV free wall longitudinal strain < 14.35% in absolute value was associated with arrhythmic outcomes (p = 0.033). CONCLUSION: Our data suggest that ECHO's advanced techniques improve ARVC detection and that abnormal RV strain can be associated with arrhythmic risk stratification. Further studies are necessary to better demonstrate these findings and contribute to risk stratification in ARVC, in addition to other well-known risk markers.

Altered sleep architecture in diabetes and prediabetes: findings from the Baependi Heart Study.

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.

Before and after AlphaFold2: An overview of protein structure prediction.

Three-dimensional protein structure is directly correlated with its function and its determination is critical to understanding biological processes and addressing human health and life science problems in general. Although new protein structures are experimentally obtained over time, there is still a large difference between the number of protein sequences placed in Uniprot and those with resolved tertiary structure. In this context, studies have emerged to predict protein structures by methods based on a template or free modeling. In the last years, different methods have been combined to overcome their individual limitations, until the emergence of AlphaFold2, which demonstrated that predicting protein structure with high accuracy at unprecedented scale is possible. Despite its current impact in the field, AlphaFold2 has limitations. Recently, new methods based on protein language models have promised to revolutionize the protein structural biology allowing the discovery of protein structure and function only from evolutionary patterns present on protein sequence. Even though these methods do not reach AlphaFold2 accuracy, they already covered some of its limitations, being able to predict with high accuracy more than 200 million proteins from metagenomic databases. In this mini-review, we provide an overview of the breakthroughs in protein structure prediction before and after AlphaFold2 emergence.

Altered sleep architecture in diabetes and prediabetes: findings from the Baependi Heart Study.

Objective: People with diabetes are more likely to have obstructive sleep apnea, but there are few studies examining sleep architecture in people with diabetes, especially in the absence of moderate-severe sleep apnea. Therefore, we compared sleep architecture among people with diabetes, prediabetes or neither condition, whilst excluding people with moderate-severe sleep apnea. Research design and methods: This sample is from the Baependi Heart Study, a prospective, family-based cohort of adults in Brazil. 1,074 participants underwent at-home polysomnography (PSG). Diabetes was defined as 1) FBG>125 OR 2) HbA1c>6.4 OR 3) taking diabetic medication, and prediabetes was defined as 1) [(5.7≤HbA1c≤6.4) OR (100≤FBG≤125)] AND 2) not taking diabetic medication. We excluded participants that had an apnea-hypopnea index (AHI)>30 from these analyses to reduce confounding due to severe sleep apnea. We compared sleep stages among the 3 groups. Results: Compared to those without diabetes, we found shorter REM duration for participants with diabetes (-6.7min, 95%CI -13.2, -0.1) or prediabetes (-5.9min, 95%CI -10.5, -1.3), even after adjusting for age, gender, BMI, and AHI. Diabetes was also associated with lower total sleep time (-13.7min, 95%CI -26.8, -0.6), longer slow-wave sleep (N3) duration (+7.6min, 95%CI 0.6, 14.6) and higher N3 percentage (+2.4%, 95%CI 0.6, 4.2), compared to those without diabetes. Conclusions: People with diabetes and prediabetes had less REM sleep after taking into account potential confounders, including AHI. People with diabetes also had more N3 sleep. These results suggest that diabetes is associated with different sleep architecture, even in the absence of moderate-severe sleep apnea.

Cardiomyocyte infection by Trypanosoma cruzi promotes innate immune response and glycolysis activation.

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.

Cardiovascular disease onset in old people with severe hypercholesterolemia.

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.

mTOR signaling inhibition decreases lysosome migration and impairs the success of Trypanosoma cruzi infection and replication in cardiomyocytes.

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.

Erratum: Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100099.].

Genome-wide analyses identify SCN5A as a susceptibility locus for premature atrial contraction frequency.

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.

Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature.

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.

Time-regulated transcripts with the potential to modulate human pluripotent stem cell-derived cardiomyocyte differentiation.

BACKGROUND: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising disease model, even though hiPSC-CMs cultured for extended periods display an undifferentiated transcriptional landscape. MiRNA-target gene interactions contribute to fine-tuning the genetic program governing cardiac maturation and may uncover critical pathways to be targeted. METHODS: We analyzed a hiPSC-CM public dataset to identify time-regulated miRNA-target gene interactions based on three logical steps of filtering. We validated this process in silico using 14 human and mouse public datasets, and further confirmed the findings by sampling seven time points over a 30-day protocol with a hiPSC-CM clone developed in our laboratory. We then added miRNA mimics from the top eight miRNAs candidates in three cell clones in two different moments of cardiac specification and maturation to assess their impact on differentiation characteristics including proliferation, sarcomere structure, contractility, and calcium handling. RESULTS: We uncovered 324 interactions among 29 differentially expressed genes and 51 miRNAs from 20,543 transcripts through 120 days of hiPSC-CM differentiation and selected 16 genes and 25 miRNAs based on the inverse pattern of expression (Pearson R-values < - 0.5) and consistency in different datasets. We validated 16 inverse interactions among eight genes and 12 miRNAs (Person R-values < - 0.5) during hiPSC-CMs differentiation and used miRNAs mimics to verify proliferation, structural and functional features related to maturation. We also demonstrated that miR-124 affects Ca2+ handling altering features associated with hiPSC-CMs maturation. CONCLUSION: We uncovered time-regulated transcripts influencing pathways affecting cardiac differentiation/maturation axis and showed that the top-scoring miRNAs indeed affect primarily structural features highlighting their role in the hiPSC-CM maturation.

Different Transcriptomic Response to T. cruzi Infection in hiPSC-Derived Cardiomyocytes From Chagas Disease Patients With and Without Chronic Cardiomyopathy.

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.

Plasma Ceramides in Cardiovascular Disease Risk Stratification. / Ceramidas Plasmáticas na Estratificação de Risco das Doenças Cardiovasculares.

Ceramide production takes place throughout the body and plays a key role in the maintenance of normal physiology. However, ceramide levels are altered during disease states, particularly considering the development of diabetes and dyslipidemia. Ceramide production is also associated with atherosclerotic plaque instability. Recent studies revealed that patients with unstable coronary artery disease (CAD) presented increased plasma ceramide levels (especially C16, C18, and C24:1). These molecules are currently considered emerging biomarkers of cardiovascular diseases (CVD), being used for predicting atherosclerotic plaque instability and adverse cardiovascular events independently from traditional risk factors. With the aim of describing and discussing the role of ceramides in the stratification of cardiovascular diseases, this narrative review contextualizes the importance of this biomarker in the present cardiology scenario.

A produção de ceramida ocorre em todo o corpo e desempenha um papel importante na manutenção da fisiologia normal. No entanto, os níveis de ceramidas são alterados em estados de doença, principalmente durante o desenvolvimento de diabetes e dislipidemia. A produção de ceramidas também está associada à instabilidade das placas ateroscleróticas. Estudos recentes revelam que pacientes com doença arterial coronariana instável apresentam níveis plasmáticos aumentados de ceramidas (principalmente C16, C18 e C24:1). Atualmente, são consideradas biomarcadores emergentes nas doenças cardiovasculares, sendo utilizadas na predição de instabilidade da placa aterosclerótica e eventos cardiovasculares adversos de forma independente aos fatores de risco tradicionais. Com o objetivo de descrever e discutir o papel das ceramidas na estratificação das doenças cardiovasculares, o desenvolvimento desta revisão narrativa contextualiza a importância desse biomarcador no cenário atual da cardiologia.

Blockchain-Based Architecture Design for Personal Health Record: Development and Usability Study.

BACKGROUND: The importance of blockchain-based architectures for personal health record (PHR) lies in the fact that they are thought and developed to allow patients to control and at least partly collect their health data. Ideally, these systems should provide the full control of such data to the respective owner. In spite of this importance, most of the works focus more on describing how blockchain models can be used in a PHR scenario rather than whether these models are in fact feasible and robust enough to support a large number of users. OBJECTIVE: To achieve a consistent, reproducible, and comparable PHR system, we build a novel ledger-oriented architecture out of a permissioned distributed network, providing patients with a manner to securely collect, store, share, and manage their health data. We also emphasize the importance of suitable ledgers and smart contracts to operate the blockchain network as well as discuss the necessity of standardizing evaluation metrics to compare related (net)works. METHODS: We adopted the Hyperledger Fabric platform to implement our blockchain-based architecture design and the Hyperledger Caliper framework to provide a detailed assessment of our system: first, under workload, ranging from 100 to 2500 simultaneous record submissions, and second, increasing the network size from 3 to 13 peers. In both experiments, we used throughput and average latency as the primary metrics. We also created a health database, a cryptographic unit, and a server to complement the blockchain network. RESULTS: With a 3-peer network, smart contracts that write on the ledger have throughputs, measured in transactions per second (tps) in an order of magnitude close to 102 tps, while those contracts that only read have rates close to 103 tps. Smart contracts that write also have latencies, measured in seconds, in an order of magnitude close to 101 seconds, while that only read have delays close to 100 seconds. In particular, smart contracts that retrieve, list, and view history have throughputs varying, respectively, from 1100 tps to 1300 tps, 650 tps to 750 tps, and 850 tps to 950 tps, impacting the overall system response if they are equally requested under the same workload. Varying the network size and applying an equal fixed load, in turn, writing throughputs go from 102 tps to 101 tps and latencies go from 101 seconds to 102 seconds, while reading ones maintain similar values. CONCLUSIONS: To the best of our knowledge, we are the first to evaluate, using Hyperledger Caliper, the performance of a PHR blockchain architecture and the first to evaluate each smart contract separately. Nevertheless, blockchain systems achieve performances far below what the traditional distributed databases achieve, indicating that the assessment of blockchain solutions for PHR is a major concern to be addressed before putting them into a real production.

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

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.

Genetic risk factors and COVID-19 severity in Brazil: results from BRACOVID study.

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.

Ceramidas Plasmáticas na Estratificação de Risco das Doenças Cardiovasculares / Plasma Ceramides in Cardiovascular Disease Risk Stratification

Resumo A produção de ceramida ocorre em todo o corpo e desempenha um papel importante na manutenção da fisiologia normal. No entanto, os níveis de ceramidas são alterados em estados de doença, principalmente durante o desenvolvimento de diabetes e dislipidemia. A produção de ceramidas também está associada à instabilidade das placas ateroscleróticas. Estudos recentes revelam que pacientes com doença arterial coronariana instável apresentam níveis plasmáticos aumentados de ceramidas (principalmente C16, C18 e C24:1). Atualmente, são consideradas biomarcadores emergentes nas doenças cardiovasculares, sendo utilizadas na predição de instabilidade da placa aterosclerótica e eventos cardiovasculares adversos de forma independente aos fatores de risco tradicionais. Com o objetivo de descrever e discutir o papel das ceramidas na estratificação das doenças cardiovasculares, o desenvolvimento desta revisão narrativa contextualiza a importância desse biomarcador no cenário atual da cardiologia.

Abstract Ceramide production takes place throughout the body and plays a key role in the maintenance of normal physiology. However, ceramide levels are altered during disease states, particularly considering the development of diabetes and dyslipidemia. Ceramide production is also associated with atherosclerotic plaque instability. Recent studies revealed that patients with unstable coronary artery disease (CAD) presented increased plasma ceramide levels (especially C16, C18, and C24:1). These molecules are currently considered emerging biomarkers of cardiovascular diseases (CVD), being used for predicting atherosclerotic plaque instability and adverse cardiovascular events independently from traditional risk factors. With the aim of describing and discussing the role of ceramides in the stratification of cardiovascular diseases, this narrative review contextualizes the importance of this biomarker in the present cardiology scenario.

Pharmacological treatment with lipid-lowering agents after molecular identification of familial hypercholesterolemia: results from the Hipercol Brasil cohort.

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.