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1.
Circ Genom Precis Med ; : 101161CIRCGEN121003507, 2022 May 10.
Article in English | MEDLINE | ID: mdl-35536239

ABSTRACT

BACKGROUND: Truncating variants in the desmosomal gene PKP2 (PKP2tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity. METHODS: We identified individuals with PKP2tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The PKP2tv 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) were assessed. RESULTS: PKP2tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique PKP2tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with PKP2tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10-4). The ARVC cohort included 487 ARVC probands with 144 distinct PKP2tv, with 25 PKP2tv common to both cohorts. The odds ratio for ARVC for the 25 common PKP2tv 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 PKP2tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with PKP2tv (7.9% versus 4.3%; odds ratio, 2.11; P=0.005). CONCLUSIONS: PKP2tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how PKP2tv cause ARVC in combination with associated genetic and environmental risk factors.

2.
HGG Adv ; 3(2): 100099, 2022 Apr 14.
Article in English | MEDLINE | ID: mdl-35399580

ABSTRACT

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.

3.
Clinics (Sao Paulo) ; 77: 100013, 2022.
Article in English | MEDLINE | ID: mdl-35397368

ABSTRACT

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/m2) (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.


Subject(s)
Atherosclerosis , Cardiovascular Diseases , Hypertension , Atherosclerosis/epidemiology , Biomarkers , Cardiovascular Diseases/epidemiology , Carotid Intima-Media Thickness , Cohort Studies , Female , Humans , Male , Risk Factors
5.
Hum Mol Genet ; 2022 Apr 02.
Article in English | MEDLINE | ID: mdl-35368071

ABSTRACT

The 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 in 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.

6.
J Heart Lung Transplant ; 2022 Feb 03.
Article in English | MEDLINE | ID: mdl-35317953

ABSTRACT

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.

7.
J Clin Lipidol ; 16(2): 198-207, 2022.
Article in English | MEDLINE | ID: mdl-35181259

ABSTRACT

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.


Subject(s)
Hyperlipoproteinemia Type II , Adult , Brazil/epidemiology , Cholesterol, LDL , Humans , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/genetics , Prospective Studies , Risk Factors
8.
Circ Genom Precis Med ; 15(2): e003500, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35130025

ABSTRACT

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.


Subject(s)
Diabetes Mellitus , Heart Defects, Congenital , Body Mass Index , Child , Female , Gene Regulatory Networks , Heart Defects, Congenital/epidemiology , Humans , Infant , Infant, Newborn , Mothers , Obesity/complications , Obesity/genetics , Pregnancy
9.
Sleep Health ; 8(2): 167-174, 2022 04.
Article in English | MEDLINE | ID: mdl-34924345

ABSTRACT

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.


Subject(s)
COVID-19 , Aged , Brazil/epidemiology , Cross-Sectional Studies , Female , Humans , Male , Pandemics , Rural Population , SARS-CoV-2
10.
Front Genet ; 12: 728526, 2021.
Article in English | MEDLINE | ID: mdl-34659352

ABSTRACT

Pharmacological inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9) is an established therapeutic option to treat hypercholesterolemia, and plasma PCSK9 levels have been implicated in cardiovascular disease incidence. A number of genetic variants within the PCSK9 gene locus have been shown to modulate PCSK9 levels, but these only explain a very small percentage of the overall PCSK9 interindividual variation. Here we present data on the genetic association structure between PCSK9 levels and genom-wide genetic variation in a healthy sample from the general population. We performed a genome-wide association study of plasma PCSK9 levels in a sample of Brazilian individuals enrolled in the Estudo Longitudinal de Saude do Adulto cohort (n=810). Enrolled individuals were free from cardiovascular disease, diabetes and were not under lipid-lowering medication. Genome-wide genotyping was conducted using the Axiom_PMRA.r3 array, and imputation was performed using the TOPMED multi-ancestry sample panel as reference. Total PCSK9 plasma concentrations were determined using the Quantikine SPC900 ELISA kit. We observed two genome-wide significant loci and seven loci that reached the pre-defined value of p threshold of 1×10-6. Significant variants were near KCNA5 and KCNA1, and LINC00353. Genetic variation at the PCSK9 locus was able to explain approximately 4% of the overall interindividual variations in PCSK9 levels. Colocalization analysis using eQTL data suggested RWDD3, ATXN7L1, KCNA1, and FAM177A1 to be potential mediators of some of the observed associations. Our results suggest that PCSK9 levels may be modulated by trans genetic variation outside of the PCSK9 gene and this may have clinical implications. Understanding both environmental and genetic predictors of PCSK9 levels may help identify new targets for cardiovascular disease treatment and contribute to a better assessment of the benefits of long-term PCSK9 inhibition.

11.
J Clin Invest ; 131(23)2021 12 01.
Article in English | MEDLINE | ID: mdl-34597274

ABSTRACT

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.


Subject(s)
Alleles , COVID-19 , Chromosomes, Human, Pair 3/genetics , Gene Frequency , Genetic Loci , Polymorphism, Genetic , SARS-CoV-2 , Age Factors , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/mortality , Female , Humans , Male , Middle Aged , Patient Acuity , Risk Factors
12.
Nat Med ; 27(10): 1818-1824, 2021 10.
Article in English | MEDLINE | ID: mdl-34556856

ABSTRACT

Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.


Subject(s)
Cardiomyopathy, Hypertrophic/drug therapy , Heart Failure/drug therapy , Heart/drug effects , Valsartan/administration & dosage , Adolescent , Adult , Cardiomyopathy, Hypertrophic/physiopathology , Double-Blind Method , Female , Heart/physiopathology , Heart Failure/physiopathology , Humans , Male , Middle Aged , Valsartan/adverse effects , Young Adult
13.
Aging (Albany NY) ; 13(17): 20992-21008, 2021 09 07.
Article in English | MEDLINE | ID: mdl-34493690

ABSTRACT

Despite the well-established association of gene expression deregulation with low muscle mass (LMM), the associated biological mechanisms remain unclear. Transcriptomic studies are capable to identify key mediators in complex diseases. We aimed to identify relevant mediators and biological mechanisms associated with age-related LMM. LMM-associated genes were detected by logistic regression using microarray data of 20 elderly women with LMM and 20 age and race-matched controls extracted from our SPAH Study (GSE152073). We performed weighted gene co-expression analysis (WGCNA) that correlated the identified gene modules with laboratorial characteristics. Gene enrichment analysis was performed and an LMM predictive model was constructed using Support Vector Machine (SVM). Overall, 821 discriminating transcripts clusters were identified (|beta coefficient| >1; p-value <0.01). From this list, 45 predictors of LMM were detected by SVM and validated with 0.7 of accuracy. Our results revealed that the well-described association of inflammation, immunity and metabolic alterations is also relevant at transcriptomic level. WGCNA highlighted a correlation of genes modules involved in immunity pathways with vitamin D level (R = 0.63, p = 0.004) and the Agatston score (R = 0.51, p = 0.02). Our study generated a predicted regulatory network and revealed significant metabolic pathways related to aging processes, showing key mediators that warrant further investigation.


Subject(s)
Aging , Gene Regulatory Networks , Immune System , Inflammation , Muscle, Skeletal , Sarcopenia/metabolism , Transcriptome , Aged , Aged, 80 and over , Female , Gene Expression Profiling , Humans , Inflammation/genetics , Inflammation/metabolism , Logistic Models , Metabolic Networks and Pathways , Sarcopenia/genetics , Support Vector Machine , Vitamin D/blood
14.
Sci Rep ; 11(1): 17764, 2021 09 07.
Article in English | MEDLINE | ID: mdl-34493753

ABSTRACT

Endothelial-mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7 (MAPK7) inhibits EndMT and decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (EZH2), thereby maintaining endothelial quiescence. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). It is elusive how the crosstalk between MAPK7 and EZH2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed in vascular disease. In human coronary artery disease, we assessed the expression levels of MAPK7 and EZH2 and found that with increasing intima/media thickness ratio, MAPK7 expression decreased, whereas EZH2 expression increased. In vitro, MAPK7 activation decreased EZH2 expression, whereas endothelial cells deficient of EZH2 had increased MAPK7 activity. MAPK7 activation results in increased expression of microRNA (miR)-101, a repressor of EZH2. This loss of EZH2 in turn results in the increased expression of the miR-200 family, culminating in decreased expression of the dual-specificity phosphatases 1 and 6 who may repress MAPK7 activity. Transfection of endothelial cells with miR-200 family members decreased the endothelial sensitivity to TGFß1-induced EndMT. In endothelial cells there is reciprocity between MAPK7 signaling and EZH2 expression and disturbances in this reciprocal signaling associate with the induction of EndMT and severity of human coronary artery disease.


Subject(s)
Cell Transdifferentiation/physiology , Coronary Artery Disease/pathology , Endothelium, Vascular/pathology , Enhancer of Zeste Homolog 2 Protein/physiology , Mesoderm/pathology , Mitogen-Activated Protein Kinase 7/physiology , Signal Transduction/physiology , Tunica Intima/pathology , 3' Untranslated Regions/genetics , Coronary Artery Disease/enzymology , Coronary Stenosis/enzymology , Coronary Stenosis/pathology , Dual Specificity Phosphatase 1/biosynthesis , Dual Specificity Phosphatase 1/genetics , Dual Specificity Phosphatase 6/biosynthesis , Dual Specificity Phosphatase 6/genetics , Endothelium, Vascular/enzymology , Enzyme Activation , Gene Expression Regulation , Genes, Reporter , Histone Code , Human Umbilical Vein Endothelial Cells , Humans , Hyperplasia , Mesoderm/enzymology , MicroRNAs/biosynthesis , MicroRNAs/genetics , Tunica Media/pathology
15.
Eur Heart J ; 42(38): 3932-3944, 2021 10 07.
Article in English | MEDLINE | ID: mdl-34491319

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic , Defibrillators, Implantable , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/therapy , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/prevention & control , Humans , Primary Prevention , Risk Assessment , Risk Factors
16.
J Biol Rhythms ; 36(5): 483-490, 2021 10.
Article in English | MEDLINE | ID: mdl-34313481

ABSTRACT

It is well established that the oldest chronotype questionnaire, the morningness-eveningness questionnaire (MEQ), has significant heritability, and several associations have been reported between MEQ score and polymorphisms in candidate clock genes, a number of them reproducibly across populations. By contrast, there are no reports of heritability and genetic associations for the Munich chronotype questionnaire (MCTQ). Recent genome-wide association studies (GWAS) from large cohorts have reported multiple associations with chronotype as assessed by a single self-evaluation question. We have taken advantage of the availability of data from all these instruments from a single sample of 597 participants from the Brazilian Baependi Heart Study. The family-based design of the cohort allowed us to calculate the heritability (h2) for these measures. Heritability values for the best-fitted models were 0.37 for MEQ, 0.32 for MCTQ, and 0.28 for single-question chronotype (MEQ Question 19). We also calculated the heritability for the two major factors recently derived from MEQ, "Dissipation of sleep pressure" (0.32) and "Build-up of sleep pressure" (0.28). This first heritability comparison of the major chronotype instruments in current use provides the first quantification of the genetic component of MCTQ score, supporting its future use in genetic analysis. Our findings also suggest that the single chronotype question that has been used for large GWAS analyses captures a larger proportion of the dimensions of chronotype than previously thought.


Subject(s)
Circadian Rhythm , Genome-Wide Association Study , Circadian Rhythm/genetics , Cohort Studies , Humans , Sleep/genetics , Surveys and Questionnaires
17.
Epigenomics (Online) ; 13(10): 779-791, May., 2021.
Article in English | SES-SP, SES-SP, CONASS, SESSP-IDPCPROD, SES-SP | ID: biblio-1247328

ABSTRACT

AIM: functional analysis of pcsk9 3'utr variants and mrna-mirna interactions were explored in patients with familial hypercholesterolemia (fh). MATERIALS & METHODS: PCSK9 3'UTR variants were identified by exon-targeted gene sequencing. Functional effects of 3'UTR variants and mRNA-miRNA interactions were analyzed using in silico and in vitro studies in HEK293FT and HepG2 cells. RESULTS: Twelve PCSK9 3'UTR variants were detected in 88 FH patients. c.*75C >T and c.*345C >T disrupted interactions with miR-6875, miR-4721 and miR-564. Transient transfection of the c.*345C >T decreased luciferase activity in HEK293FT cells. miR-4721 and miR-564 mimics reduced PCSK9 expression in HepG2 cells. CONCLUSION: PCSK9 c.*345C >T has a possible role as loss-of-function variant. miR-4721 and miR-564 downregulate PCSK9 and may be useful to improve lipid profile in FH patients.


Subject(s)
MicroRNAs , Epigenomics , Hyperlipoproteinemia Type II , Proprotein Convertase 9
18.
Nutr Metab Cardiovasc Dis ; 31(7): 2014-2022, 2021 06 30.
Article in English | MEDLINE | ID: mdl-34039501

ABSTRACT

BACKGROUND AND AIMS: Familial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH. This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP). METHODS AND RESULTS: In this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135-250) and 161 (133-193) mg/dL; 141 (109-181) and 103 (88-134) mg/dL; and 1.6 (0.8-4.0) and 0.8 (0.4-1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies. CONCLUSIONS: Higher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH.


Subject(s)
Cardiovascular Diseases/prevention & control , Diet, Healthy , Diet, Mediterranean , Hyperlipoproteinemia Type II/diet therapy , Inflammation Mediators/blood , Inflammation/prevention & control , Lipids/blood , Patient Compliance , Risk Reduction Behavior , Adult , Biomarkers/blood , Brazil/epidemiology , Cardiovascular Diseases/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cross-Sectional Studies , Feeding Behavior , Female , Heart Disease Risk Factors , Humans , Hyperlipoproteinemia Type II/blood , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/epidemiology , Inflammation/blood , Inflammation/diagnosis , Inflammation/epidemiology , Male , Middle Aged , Nutritive Value , Protective Factors , Risk Assessment , Spain/epidemiology , Time Factors , Treatment Outcome
19.
Epigenomics ; 13(10): 779-791, 2021 05.
Article in English | MEDLINE | ID: mdl-33899508

ABSTRACT

Aim: Functional analysis of PCSK9 3'UTR variants and mRNA-miRNA interactions were explored in patients with familial hypercholesterolemia (FH). Materials & methods: PCSK9 3'UTR variants were identified by exon-targeted gene sequencing. Functional effects of 3'UTR variants and mRNA-miRNA interactions were analyzed using in silico and in vitro studies in HEK293FT and HepG2 cells. Results: Twelve PCSK9 3'UTR variants were detected in 88 FH patients. c.*75C >T and c.*345C >T disrupted interactions with miR-6875, miR-4721 and miR-564. Transient transfection of the c.*345C >T decreased luciferase activity in HEK293FT cells. miR-4721 and miR-564 mimics reduced PCSK9 expression in HepG2 cells. Conclusion: PCSK9 c.*345C >T has a possible role as loss-of-function variant. miR-4721 and miR-564 downregulate PCSK9 and may be useful to improve lipid profile in FH patients.


Subject(s)
Hyperlipoproteinemia Type II/genetics , MicroRNAs , Proprotein Convertase 9/genetics , RNA, Messenger , 3' Untranslated Regions , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Genetic Variation , HEK293 Cells , Hep G2 Cells , Humans , Hyperlipoproteinemia Type II/metabolism , Male , Middle Aged , Proprotein Convertase 9/metabolism , Young Adult
20.
Hypertension ; 71(4): 681-690, Apr. 2018. tab, ilus, graf
Article in English | SES-SP, SES-SP, CONASS, SESSP-IDPCPROD, SES-SP | ID: biblio-1177508

ABSTRACT

ABSTRACT: The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy.


Subject(s)
Spironolactone , Clonidine , Drug Therapy , Hypertension
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