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1.
Artigo em Inglês | MEDLINE | ID: mdl-33890823

RESUMO

Background - Genetic testing can determine family screening strategies and has prognostic and diagnostic value in hypertrophic cardiomyopathy (HCM). However, it can also pose a significant psychosocial burden. Conventional scoring systems offer modest ability to predict genotype positivity. The aim of our study was to develop a novel prediction model for genotype positivity in patients with HCM by applying machine learning (ML) algorithms. Methods - We constructed three ML models using readily available clinical and cardiac imaging data of 102 patients from Columbia University with HCM who had undergone genetic testing (the training set). We validated model performance on 76 patients with HCM from Massachusetts General Hospital (the test set). Within the test set, we compared the area under the receiver operating characteristic curves (AUCs) for the ML models against the AUCs generated by the Toronto HCM Genotype Score ("the Toronto score") and Mayo HCM Genotype Predictor ("the Mayo score") using the Delong test and net reclassification improvement (NRI). Results - Overall, 63 of the 178 patients (35%) were genotype positive. The random forest ML model developed in the training set demonstrated an AUC of 0.92 (95% CI 0.85-0.99) in predicting genotype positivity in the test set, significantly outperforming the Toronto score (AUC 0.77, 95% CI 0.65-0.90, p=0.004, NRI: p<0.001) and the Mayo score (AUC 0.79, 95% CI 0.67-0.92, p=0.01, NRI: p=0.001). The gradient boosted decision tree ML model also achieved significant NRI over the Toronto score (p<0.001) and the Mayo score (p=0.03), with an AUC of 0.87 (95% CI 0.75-0.99). Compared to the Toronto and Mayo scores, all three ML models had higher sensitivity, positive predictive value, and negative predictive value. Conclusions - Our ML models demonstrated a superior ability to predict genotype positivity in patients with HCM compared to conventional scoring systems in an external validation test set.

2.
Nature ; 592(7853): 296-301, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33731931

RESUMO

Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors1. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2V617F (JAK2VF) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1ß reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1ß or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.

3.
Eur Heart J ; 42(9): 919-933, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33532862

RESUMO

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

4.
J Clin Invest ; 131(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33630758

RESUMO

Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk allele to CAD via impaired efferocytosis. We show here that rs9349379-G/G was associated with lower levels of PHACTR1 and impaired efferocytosis in human monocyte-derived macrophages and human atherosclerotic lesional macrophages compared with rs9349379-A/A. Silencing PHACTR1 in human and mouse macrophages compromised AC engulfment, and Western diet-fed Ldlr-/- mice in which hematopoietic Phactr1 was genetically targeted showed impaired lesional efferocytosis, increased plaque necrosis, and thinner fibrous caps - all signs of vulnerable plaques in humans. Mechanistically, PHACTR1 prevented dephosphorylation of myosin light chain (MLC), which was necessary for AC engulfment. In summary, rs9349379-G lowered PHACTR1, which, by lowering phospho-MLC, compromised efferocytosis. Thus, rs9349379-G may contribute to CAD risk, at least in part, by impairing atherosclerotic lesional macrophage efferocytosis.

5.
Circ Genom Precis Med ; 13(6): e002769, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33321069

RESUMO

BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D). METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D). RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background. CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.

6.
J Subst Abuse Treat ; : 108196, 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33221125

RESUMO

The temporary loosening of regulations governing methadone and buprenorphine treatment for opioid use disorder (OUD) in the U.S., instituted to prevent the spread of COVID-19, has created an opportunity to explore the effectiveness of new models of care for people with OUD. The opioid cascade describes the current status of the treatment system, where only a fraction of people with OUD initiate effective medication treatment for OUD (MOUD), and of those only a fraction is retained in treatment. Regulatory changes-such as availability of larger take-home supplies of methadone and buprenorphine initiated via telemedicine (e.g., no initial in person visit; telemedicine buprenorphine permitted across state lines)-could modify the cascade, by reducing the burden and increasing the attractiveness, availability, and feasibility of MOUD both for people with OUD and for providers. We review examples of more liberal MOUD regimens, including the implementation of buprenorphine in France in the 1990s, primary care-based methadone in Canada, and low-threshold buprenorphine models. Research is needed to document whether new models implemented in the U.S. in the wake of COVID-19 are successful, and whether safety concerns, such as diversion and misuse, emerge. We discuss barriers to implementation, including racial and ethnic health disparities, and lack of knowledge and reluctance among potential providers of MOUD. We suggest that the urgency and public spiritedness of the response to COVID-19 be harnessed to make gains on the opioid cascade, inspiring prescribers, health systems, and communities to embrace the delivery of MOUD to meet the needs of an increasingly vulnerable population.

7.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120315045, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33176448

RESUMO

OBJECTIVE: Transcriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33-GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT, UK Biobank, GLGC, Cardiogram, and DIAGRAM/DIAMANTE. These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study-associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation. CONCLUSIONS: These findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.

8.
Int J Cardiol ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33181159

RESUMO

BACKGROUND: Only a subset of patients with hypertrophic cardiomyopathy (HCM) develop adverse cardiac events - e.g., end-stage heart failure, cardiovascular death. Current risk stratification methods are imperfect, limiting identification of high-risk patients with HCM. Our aim was to improve the prediction of adverse cardiac events in patients with HCM using machine learning methods. METHODS: We applied modern machine learning methods to a prospective cohort of adults with HCM. The outcome was a composite of death due to heart failure, heart transplant, and sudden death. As the reference model, we constructed logistic regression model using known predictors. We determined 20 predictive characteristics based on random forest classification and a priori knowledge, and developed 4 machine learning models. Results Of 183 patients in the cohort, the mean age was 53 (SD = 17) years and 45% were female. During the median follow-up of 2.2 years (interquartile range, 0.6-3.8), 33 subjects (18%) developed an outcome event, the majority of which (85%) was heart transplant. The predictive accuracy of the reference model was 73% (sensitivity 76%, specificity 72%) while that of the machine learning model was 85% (e.g., sensitivity 88%, specificity 84% with elastic net regression). All 4 machine learning models significantly outperformed the reference model - e.g., area under the receiver-operating-characteristic curve 0.79 with the reference model vs. 0.93 with elastic net regression (p < 0.001). CONCLUSIONS: Compared with conventional risk stratification, the machine learning models demonstrated a superior ability to predict adverse cardiac events. These modern machine learning methods may enhance identification of high-risk HCM subpopulations.

9.
J Clin Invest ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32931480

RESUMO

BACKGROUND: The ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases including Acute Respiratory Distress Syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation. METHODS: We conducted analyses in three cohorts of critically ill trauma and sepsis patients (n = 3,710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined if associations were present in FUT2 defined non-secretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested if blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP). RESULTS: The A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all three populations. In sepsis, this relationship was strongest in non-pulmonary infections. The association persisted in non-secretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand Factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP. CONCLUSIONS: We identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill possibly mediated through microvascular dysfunction and coagulation.

10.
Circulation ; 142(21): 2060-2075, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-32962412

RESUMO

BACKGROUND: Smooth muscle cells (SMCs) play significant roles in atherosclerosis via phenotypic switching, a pathological process in which SMC dedifferentiation, migration, and transdifferentiation into other cell types. Yet how SMCs contribute to the pathophysiology of atherosclerosis remains elusive. METHODS: To reveal the trajectories of SMC transdifferentiation during atherosclerosis and to identify molecular targets for disease therapy, we combined SMC fate mapping and single-cell RNA sequencing of both mouse and human atherosclerotic plaques. We also performed cell biology experiments on isolated SMC-derived cells, conducted integrative human genomics, and used pharmacological studies targeting SMC-derived cells both in vivo and in vitro. RESULTS: We found that SMCs transitioned to an intermediate cell state during atherosclerosis, which was also found in human atherosclerotic plaques of carotid and coronary arteries. SMC-derived intermediate cells, termed "SEM" cells (stem cell, endothelial cell, monocyte), were multipotent and could differentiate into macrophage-like and fibrochondrocyte-like cells, as well as return toward the SMC phenotype. Retinoic acid (RA) signaling was identified as a regulator of SMC to SEM cell transition, and RA signaling was dysregulated in symptomatic human atherosclerosis. Human genomics revealed enrichment of genome-wide association study signals for coronary artery disease in RA signaling target gene loci and correlation between coronary artery disease risk alleles and repressed expression of these genes. Activation of RA signaling by all-trans RA, an anticancer drug for acute promyelocytic leukemia, blocked SMC transition to SEM cells, reduced atherosclerotic burden, and promoted fibrous cap stability. CONCLUSIONS: Integration of cell-specific fate mapping, single-cell genomics, and human genetics adds novel insights into the complexity of SMC biology and reveals regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.

12.
Artigo em Inglês | MEDLINE | ID: mdl-32594362

RESUMO

It is unclear how hypertrophic cardiomyopathy (HCM) affects cardiac metabolic pathways at rest and with exercise. This case-control study compared 15 cases with HCM to 2 control groups without HCM. Metabolomic profiling of 210 metabolites was carried out at rest and at peak exercise. The 50 most discriminant metabolites differentially regulated during exercise were selected using partial least squares discriminant analysis. Pathway enrichment analysis was also performed. At rest, no significant difference was observed in metabolomic profiling of HCM cases as compared to controls. By contrast, there were significant differences in metabolomic profiling in response to exercise (p < 0.05) in the following metabolic pathways: the aminoacyl-tRNA biosynthesis pathway; the nitrogen metabolism pathway; the glycine, serine, and threonine metabolism pathway; and the arginine and proline metabolism pathway. The present study demonstrates differential regulation of several metabolic pathways in patients with HCM in the setting of exercise stress.

13.
Circ Heart Fail ; 13(7): e006570, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32507024

RESUMO

BACKGROUND: NPs (natriuretic peptides) are cardiac-derived hormones that promote natriuresis, diuresis, and vasodilation. Preclinical evidence suggests that nonhemodynamic triggers for NP release exist, with a few studies implicating inflammatory stimuli. We examined the association between inflammation and NP levels in humans. METHODS: The associations between inflammation and NP levels were examined in 3 independent studies. First, in 5481 MESA (Multi-Ethnic Study of Atherosclerosis) participants, the cross-sectional (exam 1) and longitudinal (exams 1 to 3) associations between circulating IL6 (interleukin-6) and NT-proBNP (N terminal pro B-type natriuretic peptide) levels were examined in multivariable-adjusted models. Second, in a prospective study of 115 healthy individuals, changes in NP levels were quantified following exposure to lipopolysaccharide as an inflammatory stimulus. Third, in 13 435 hospitalized patients, the association between acute inflammatory conditions and circulating NP levels was assessed using multivariable-adjusted models. RESULTS: At the baseline MESA exam, each 1-unit higher natural log IL6 was associated with 16% higher NT-proBNP level ([95% CI, 10%-22%]; P=0.002). Each 1-unit higher baseline natural log IL6 level also associated with 6% higher NT-proBNP level ([95% CI, 1%-11%]; P=0.02) at 4-year follow-up. In the lipopolysaccharide study, median NT-proBNP levels rose from 21 pg/mL pre-lipopolysaccharide to 54 pg/mL post-lipopolysaccharide, P<0.001. In the hospitalized patient study, acute inflammatory conditions were associated with 36% higher NP levels ([95% CI, 17%-60%]; P<0.001). CONCLUSIONS: Inflammation appears to be associated with NP release. Interpretation of NP levels should therefore take into account inflammatory conditions.


Assuntos
Inflamação/sangue , Peptídeos Natriuréticos/sangue , Ensaios Clínicos como Assunto , Humanos , Inflamação/etiologia
14.
PLoS Genet ; 16(5): e1008786, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32392242

RESUMO

Allele-specific expression (ASE) analysis, which quantifies the relative expression of two alleles in a diploid individual, is a powerful tool for identifying cis-regulated gene expression variations that underlie phenotypic differences among individuals. Existing methods for gene-level ASE detection analyze one individual at a time, therefore failing to account for shared information across individuals. Failure to accommodate such shared information not only reduces power, but also makes it difficult to interpret results across individuals. However, when only RNA sequencing (RNA-seq) data are available, ASE detection across individuals is challenging because the data often include individuals that are either heterozygous or homozygous for the unobserved cis-regulatory SNP, leading to sample heterogeneity as only those heterozygous individuals are informative for ASE, whereas those homozygous individuals have balanced expression. To simultaneously model multi-individual information and account for such heterogeneity, we developed ASEP, a mixture model with subject-specific random effect to account for multi-SNP correlations within the same gene. ASEP only requires RNA-seq data, and is able to detect gene-level ASE under one condition and differential ASE between two conditions (e.g., pre- versus post-treatment). Extensive simulations demonstrated the convincing performance of ASEP under a wide range of scenarios. We applied ASEP to a human kidney RNA-seq dataset, identified ASE genes and validated our results with two published eQTL studies. We further applied ASEP to a human macrophage RNA-seq dataset, identified genes showing evidence of differential ASE between M0 and M1 macrophages, and confirmed our findings by results from cardiometabolic trait-relevant genome-wide association studies. To the best of our knowledge, ASEP is the first method for gene-level ASE detection at the population level that only requires the use of RNA-seq data. With the growing adoption of RNA-seq, we believe ASEP will be well-suited for various ASE studies for human diseases.


Assuntos
Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Locos de Características Quantitativas , Análise de Sequência de RNA/métodos , Alelos , Feminino , Regulação da Expressão Gênica , Genética Populacional , Humanos , Rim/química , Macrófagos/química , Modelos Genéticos , Software
15.
Nat Commun ; 11(1): 2338, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393754

RESUMO

Single-cell RNA sequencing (scRNA-seq) can characterize cell types and states through unsupervised clustering, but the ever increasing number of cells and batch effect impose computational challenges. We present DESC, an unsupervised deep embedding algorithm that clusters scRNA-seq data by iteratively optimizing a clustering objective function. Through iterative self-learning, DESC gradually removes batch effects, as long as technical differences across batches are smaller than true biological variations. As a soft clustering algorithm, cluster assignment probabilities from DESC are biologically interpretable and can reveal both discrete and pseudotemporal structure of cells. Comprehensive evaluations show that DESC offers a proper balance of clustering accuracy and stability, has a small footprint on memory, does not explicitly require batch information for batch effect removal, and can utilize GPU when available. As the scale of single-cell studies continues to grow, we believe DESC will offer a valuable tool for biomedical researchers to disentangle complex cellular heterogeneity.


Assuntos
Análise por Conglomerados , Aprendizado Profundo , RNA-Seq , Análise de Célula Única , Algoritmos , Animais , Medula Óssea/metabolismo , Regulação da Expressão Gênica , Humanos , Ilhotas Pancreáticas/metabolismo , Leucócitos Mononucleares/metabolismo , Macaca , Camundongos , Monócitos/metabolismo , Retina/metabolismo
16.
J Clin Transl Sci ; 4(1): 22-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32257407

RESUMO

Effectively addressing public health crises requires dynamic and nimble interdisciplinary collaborations across the translational spectrum, from bench to clinic to community. The Clinical and Translational Science Award (CTSA) Program hubs are uniquely suited to facilitate interdisciplinary collaborations across universities and academic medical centers. This paper describes the activities at the Columbia University CTSA Program hub to address a current public health crisis, the opioid epidemic. Columbia's CTSA Program hub led a three-phase approach, based on the Conceptual Model of Transdisciplinary Scientific Collaboration as described by Stokols et al.: (1) a university-wide planning and brainstorming phase to identify key leaders across many domains who are influential in addressing the opioid epidemic, (2) a campus-wide and community outreach to identify all interested parties, and (3) ongoing targeted support for collaboration development. Preliminary metrics of success are interdisciplinary collaborations and grant funding. We describe recent examples of how interdisciplinary collaboration, academic-community partnership, and pilot funding contributed to the development and funding of innovative interdisciplinary research, including the New York site of the HEALing Communities initiative. The processes are now being used to support interdisciplinary approaches for other translational public health issues.

17.
Stat Methods Med Res ; 29(4): 1167-1180, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31172883

RESUMO

The mechanistic pathways linking genetic polymorphisms and complex disease traits remain largely uncharacterized. At the same time, expansive new transcriptome data resources offer unprecedented opportunity to unravel the mechanistic underpinnings of complex disease associations. Two-stage strategies involving conditioning on a single, penalized regression imputation for transcriptome association analysis have been described for cross-sectional traits. In this manuscript, we propose an alternative two-stage approach based on stochastic regression imputation that additionally incorporates error in the predictive model. Application of a bootstrap procedure offers flexibility when a closed form predictive distribution is not available. The two-stage strategy is also generalized to longitudinally measured traits, using a linear mixed effects modeling framework and a composite test statistic to evaluate whether the genetic component of gene-level expression modifies the biomarker trajectory over time. Simulations studies are performed to evaluate relative performance with respect to type-1 error rates, coverage, estimation error, and power under a range of conditions. A case study is presented to investigate the association between whole blood expression for each of five inflammasome genes with inflammatory response over time after endotoxin challenge.

18.
Arterioscler Thromb Vasc Biol ; 40(1): 45-60, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31747800

RESUMO

This review focuses on the human genetics, epidemiology, and molecular pathophysiology of sex differences in central obesity, adipose distribution, and related cardiometabolic disorders. Distribution of fat is important for cardiometabolic health, with peripheral fat depots having a protective effect and central visceral fat depots conferring a detrimental effect on health. There are important sex differences in fat distribution that are masked when studying body mass index as a measure of obesity. From epidemiological, murine, and in vitro studies, several mechanisms have been proposed to explain the sex differences in adipose distribution, including sex hormonal effects, cell-intrinsic properties, and the microenvironment in fat depots. More recently, human genetics have revealed hundreds of loci for central obesity providing disruptive opportunities for mechanistic discoveries and clinical translation. A striking feature is that over one-third of these loci have reproducible but poorly understood sexual dimorphic associations with central obesity, most having stronger effects in women. Understanding the genetic and molecular mechanisms of adipose distribution and its sexual dimorphism in humans provides a unique opportunity to promote the use of precision medicine for early identification of at-risk individuals, and the development of novel therapeutic strategies for central obesity and related cardiometabolic disorders.


Assuntos
Tecido Adiposo/metabolismo , Doenças Cardiovasculares/genética , Genômica/métodos , Obesidade Abdominal/genética , Medicina de Precisão/métodos , Medição de Risco/métodos , Animais , Distribuição da Gordura Corporal , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Saúde Global , Humanos , Incidência , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia , Fatores Sexuais
19.
Arterioscler Thromb Vasc Biol ; 39(12): 2480-2491, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31645127

RESUMO

OBJECTIVE: LIPA (lysosomal acid lipase) mediates cholesteryl ester hydrolysis, and patients with rare loss-of-function mutations develop hypercholesterolemia and severe disease. Genome-wide association studies of coronary artery disease have identified several tightly linked, common intronic risk variants in LIPA which unexpectedly associate with increased mRNA expression. However, an exonic variant (rs1051338 resulting in T16P) in linkage with intronic variants lies in the signal peptide region and putatively disrupts trafficking. We sought to functionally investigate the net impact of this locus on LIPA and whether rs1051338 could disrupt LIPA processing and function to explain coronary artery disease risk. Approach and Results: In monocytes isolated from a large cohort of healthy individuals, we demonstrate both exonic and intronic risk variants are associated with increased LIPA enzyme activity coincident with the increased transcript levels. To functionally isolate the impact of rs1051338, we studied several in vitro overexpression systems and consistently observed no differences in LIPA expression, processing, activity, or secretion. Further, we characterized a second common exonic coding variant (rs1051339), which is predicted to alter LIPA signal peptide cleavage similarly to rs1051338, yet is not linked to intronic variants. rs1051339 also does not impact LIPA function in vitro and confers no coronary artery disease risk. CONCLUSIONS: Our findings show that common LIPA exonic variants in the signal peptide are of minimal functional significance and suggest coronary artery disease risk is instead associated with increased LIPA function linked to intronic variants. Understanding the mechanisms and cell-specific contexts of LIPA function in the plaque is necessary to understand its association with cardiovascular risk.


Assuntos
Doença da Artéria Coronariana/genética , DNA/genética , Mutação , Esterol Esterase/genética , Adulto , Doença da Artéria Coronariana/metabolismo , Análise Mutacional de DNA , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Fenótipo , Esterol Esterase/metabolismo , Adulto Jovem
20.
Am J Cardiol ; 124(8): 1272-1278, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31447010

RESUMO

Alcohol septal ablation (ASA) and ventricular septal myectomy (VSM) are 2 options of ventricular septal reduction therapy (VSRT) for obstructive hypertrophic cardiomyopathy (HC). We hypothesized that patients with HC who underwent ASA have a higher risk of acute care use (i.e., emergency department [ED] visit or unplanned hospitalization) for cardiovascular disease (CVD) than VSM. We performed a comparative effectiveness study of ASA versus VSM (reference group) among patients with HC who underwent VSRT, using population-based ED and inpatient databases in 3 states, 2005 to 2014. The outcome was acute care use for CVD during a 2-year post-VSRT period. We constructed univariable and multivariable logistic regression models to compare the risk during sequential 6-month periods. We also performed sensitivity analysis with propensity score-matching at 1:1 ratio. We identified 850 patients with HC who underwent VSRT, including 393 with ASA and 457 with VSM. During 13 to 18 months after VSRT, there was a nonsignificantly higher risk with ASA than VSM (adjusted odds ratio [OR] 1.73; 95% confidence interval [CI] 0.83 to 3.60; p = 0.14). Patients who had ASA had a significantly higher risk in the 19 to 24 months post-VSRT period (adjusted OR 2.12; 95% CI 1.06 to 4.23; p = 0.03). Similarly, the propensity score-matched analysis demonstrated a higher risk with ASA than VSM during 13 to 18 months (OR 2.97; 95% CI 1.04 to 8.46; p = 0.04) and 19 to 24 months (OR 7.06; 95% CI 2.04 to 24.36; p = 0.002) after VSRT. In conclusion, among 850 patients with HC who underwent VSRT, the risk of acute care use for CVD was higher after ASA than VSM during the second post-VSRT year.


Assuntos
Técnicas de Ablação/métodos , Procedimentos Cirúrgicos Cardíacos/métodos , Cardiomiopatia Hipertrófica/cirurgia , Etanol/farmacologia , Septo Interventricular/cirurgia , Adolescente , Adulto , Cardiomiopatia Hipertrófica/diagnóstico , Ecocardiografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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