Circulation: Genomic and Precision Medicine最新文献

{"title":"CYB5R3 T117S Genetic Mutation Is Associated With Major Adverse Cardiovascular and Cerebrovascular Events in Black Adults.","authors":"Rahul Chaudhary, Adam C Straub, Felix E Y Aggor, Ifeoluwa Onasanya, Jordan Richardson, Patrick J Strollo, Steven E Reis, Oladipupo Olafiranye","doi":"10.1161/CIRCGEN.123.004271","DOIUrl":"10.1161/CIRCGEN.123.004271","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004271"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiplexed Functional Assessments of <i>MYH7</i> Variants in Human Cardiomyocytes.","authors":"Clayton E Friedman, Shawn Fayer, Sriram Pendyala, Wei-Ming Chien, Alexander Loiben, Linda Tran, Leslie S Chao, Ashley McKinstry, Dania Ahmed, Stephen D Farris, April Stempien-Otero, Erica C Jonlin, Charles E Murry, Lea M Starita, Douglas M Fowler, Kai-Chun Yang","doi":"10.1161/CIRCGEN.123.004377","DOIUrl":"10.1161/CIRCGEN.123.004377","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic autosomal-dominant missense variants in <i>MYH7</i> (<i>myosin heavy chain 7</i>), which encodes the sarcomeric protein (β-MHC [beta myosin heavy chain]) expressed in cardiac and skeletal myocytes, are a leading cause of hypertrophic cardiomyopathy and are clinically actionable. However, ≈75% of <i>MYH7</i> missense variants are of unknown significance. While human-induced pluripotent stem cells (hiPSCs) can be differentiated into cardiomyocytes to enable the interrogation of <i>MYH7</i> variant effect in a disease-relevant context, deep mutational scanning has not been executed using diploid hiPSC derivates due to low hiPSC gene-editing efficiency. Moreover, multiplexable phenotypes enabling deep mutational scanning of <i>MYH7</i> variant hiPSC-derived cardiomyocytes are unknown.</p><p><strong>Methods: </strong>To overcome these obstacles, we used CRISPRa On-Target Editing Retrieval enrichment to generate an hiPSC library containing 113 <i>MYH7</i> codon variants suitable for deep mutational scanning. We first established that β-MHC protein loss occurs in a hypertrophic cardiomyopathy human heart with a pathogenic <i>MYH7</i> variant. We then differentiated the <i>MYH7</i> missense variant hiPSC library to cardiomyocytes for multiplexed assessment of β-MHC variant abundance by massively parallel sequencing and hiPSC-derived cardiomyocyte survival.</p><p><strong>Results: </strong>Both the multiplexed assessment of β-MHC abundance and hiPSC-derived cardiomyocyte survival accurately segregated all known pathogenic variants from synonymous variants. Functional data were generated for 4 variants of unknown significance and 58 additional <i>MYH7</i> missense variants not yet detected in patients.</p><p><strong>Conclusions: </strong>This study leveraged hiPSC differentiation into disease-relevant cardiomyocytes to enable multiplexed assessments of <i>MYH7</i> missense variants for the first time. Phenotyping strategies used here enable the application of deep mutational scanning to clinically actionable genes, which should reduce the burden of variants of unknown significance on patients and clinicians.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004377"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139740576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incremental Value of a Metabolic Risk Score for Heart Failure Mortality: A Population-Based Study.","authors":"Jungnam Joo, Joseph J Shearer, Anna Wolska, Alan T Remaley, James D Otvos, Margery A Connelly, Maureen Sampson, Suzette J Bielinski, Nicholas B Larson, Hoyoung Park, Katherine M Conners, Sarah Turecamo, Véronique L Roger","doi":"10.1161/CIRCGEN.123.004312","DOIUrl":"10.1161/CIRCGEN.123.004312","url":null,"abstract":"<p><strong>Background: </strong>Heart failure is heterogeneous syndrome with persistently high mortality. Nuclear magnetic resonance spectroscopy enables high-throughput metabolomics, suitable for precision phenotyping. We aimed to use targeted metabolomics to derive a metabolic risk score (MRS) that improved mortality risk stratification in heart failure.</p><p><strong>Methods: </strong>Nuclear magnetic resonance was used to measure 21 metabolites (lipoprotein subspecies, branched-chain amino acids, alanine, GlycA (glycoprotein acetylation), ketone bodies, glucose, and citrate) in plasma collected from a heart failure community cohort. The MRS was derived using least absolute shrinkage and selection operator penalized Cox regression and temporal validation. The association between the MRS and mortality and whether risk stratification was improved over the Meta-Analysis Global Group in Chronic Heart Failure clinical risk score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels were assessed.</p><p><strong>Results: </strong>The study included 1382 patients (median age, 78 years, 52% men, 43% reduced ejection fraction) with a 5-year survival rate of 48% (95% CI, 46%-51%). The MRS included 9 metabolites measured. In the validation data set, a 1 standard deviation increase in the MRS was associated with a large increased rate of death (hazard ratio, 2.2 [95% CI, 1.9-2.5]) that remained after adjustment for Meta-Analysis Global Group in Chronic Heart Failure score and NT-proBNP (hazard ratio, 1.6 [95% CI, 1.3-1.9]). These associations did not differ by ejection fraction. The integrated discrimination and net reclassification indices, and Uno's C statistic, indicated that the addition of the MRS improved discrimination over Meta-Analysis Global Group in Chronic Heart Failure and NT-proBNP.</p><p><strong>Conclusions: </strong>This MRS developed in a heart failure community cohort was associated with a large excess risk of death and improved risk stratification beyond an established risk score and clinical markers.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004312"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex Differences in the Association of Multiethnic Genome-Wide Blood Pressure Polygenic Risk Score With Population-Level Systolic Blood Pressure Trajectories.","authors":"Naman S Shetty, Akhil Pampana, Nirav Patel, Krishin Yerabolu, Gnyata Patel, Marguerite R Irvin, Pradeep Natarajan, Henry J Lin, Xiuqing Guo, Stephen S Rich, Jerome I Rotter, Peng Li, Garima Arora, Pankaj Arora","doi":"10.1161/CIRCGEN.123.004515","DOIUrl":"10.1161/CIRCGEN.123.004515","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004515"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pooled Genetic Screenings to Identify Likely Pathogenic Variants in Hypertrophic Cardiomyopathy.","authors":"Adrien Georges, Choudhary Anwar A Chahal","doi":"10.1161/CIRCGEN.124.004599","DOIUrl":"10.1161/CIRCGEN.124.004599","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004599"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy.","authors":"Vikki A Krysov, Rachel H Wilson, Nicholas S Ten, Nathan Youlton, Hannah N De Jong, Shirley Sutton, Yong Huang, Chloe M Reuter, Megan E Grove, Matthew T Wheeler, Euan A Ashley, Victoria N Parikh","doi":"10.1161/CIRCGEN.123.004370","DOIUrl":"10.1161/CIRCGEN.123.004370","url":null,"abstract":"<p><strong>Background: </strong>To realize the potential of genome engineering therapeutics, tractable strategies must be identified that balance personalized therapy with the need for off-the-shelf availability. We hypothesized that regional clustering of pathogenic variants can inform the design of rational prime editing therapeutics to treat the majority of genetic cardiovascular diseases with a limited number of reagents.</p><p><strong>Methods: </strong>We collated 2435 high-confidence pathogenic/likely pathogenic (P/LP) variants in 82 cardiovascular disease genes from ClinVar. We assessed the regional density of these variants by defining a regional clustering index. We then combined a highly active base editor with prime editing to demonstrate the feasibility of a P/LP hotspot-directed genome engineering therapeutic strategy in vitro.</p><p><strong>Results: </strong>P/LP variants in cardiovascular disease genes display higher regional density than rare variants found in the general population. P/LP missense variants displayed higher average regional density than P/LP truncating variants. Following hypermutagenesis at a pathogenic hotspot, mean prime editing efficiency across introduced variants was 57±27%.</p><p><strong>Conclusions: </strong>Designing therapeutics that target pathogenic hotspots will not only address known missense P/LP variants but also novel P/LP variants identified in these hotspots as well. Moreover, the clustering of P/LP missense rather than truncating variants in these hotspots suggests that prime editing technology is particularly valuable for dominant negative disease. Although prime editing technology in relation to cardiac health continues to improve, this study presents an approach to targeting the most impactful regions of the genome for inherited cardiovascular disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004370"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11020015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dilated Cardiomyopathy With Concomitant Salt-Losing Renal Tubulopathy Caused by Heterozygous <i>RRAGD</i> Gene Variant.","authors":"Fernando de Frutos, Carles Diez-Lopez, Elena García-Romero, Leire Gondra, Leire Madariaga, Gema Ariceta, Alejandro García-Castaño, Edoardo Melilli, Lorena Herrador, Laura Triguero-Llonch, Ferran Gran, Laia Rosenfeld, Roger Llatjos, Josep Comin-Colet, José González-Costello","doi":"10.1161/CIRCGEN.123.004336","DOIUrl":"10.1161/CIRCGEN.123.004336","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004336"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imagenetics for Precision Medicine in Dilated Cardiomyopathy.","authors":"Alexios S Antonopoulos, Anastasia Xintarakou, Alexandros Protonotarios, George Lazaros, Antigoni Miliou, Konstantinos Tsioufis, Charalambos Vlachopoulos","doi":"10.1161/CIRCGEN.123.004301","DOIUrl":"10.1161/CIRCGEN.123.004301","url":null,"abstract":"<p><p>Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as <i>DSP</i> (desmoplakin) or <i>FLNC</i> (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004301"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Guideline for Preimplantation Genetic Testing in Inherited Cardiac Diseases.","authors":"Job A J Verdonschot, Debby M E I Hellebrekers, Vanessa P M van Empel, Malou Heijligers, Sonja de Munnik, Edith Coonen, Jos C M F Dreesen, Arthur van den Wijngaard, Han G Brunner, Masoud Zamani Esteki, Stephane R B Heymans, Christine E M de Die-Smulders, Aimée D C Paulussen","doi":"10.1161/CIRCGEN.123.004416","DOIUrl":"10.1161/CIRCGEN.123.004416","url":null,"abstract":"<p><strong>Background: </strong>Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team.</p><p><strong>Methods: </strong>All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion.</p><p><strong>Results: </strong>Eighty-three couples were referred for PGT (1997-2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT.</p><p><strong>Conclusions: </strong>The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004416"},"PeriodicalIF":7.4,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11019983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Implementation of an Integrated Preclinical Atherosclerosis Database.","authors":"Rachel R Xiang, Yihua Wang, Megan M Shuey, Brigett V Carvajal, Quinn S Wells, Joshua A Beckman, Iris Z Jaffe","doi":"10.1161/CIRCGEN.123.004397","DOIUrl":"10.1161/CIRCGEN.123.004397","url":null,"abstract":"<p><strong>Background: </strong>Basic scientists have used preclinical animal models to explore mechanisms driving human diseases for decades, resulting in thousands of publications, each supporting causative inferences. Despite substantial advances in the mechanistic construct of disease, there has been limited translation from individual studies to advances in clinical care. An integrated approach to these individual studies has the potential to improve translational success.</p><p><strong>Methods: </strong>Using atherosclerosis as a test case, we extracted data from the 2 most common mouse models of atherosclerosis (ApoE [apolipoprotein E]-knockout and LDLR [low-density lipoprotein receptor]-knockout). We restricted analyses to manuscripts published in 2 well-established journals, <i>Arteriosclerosis, Thrombosis, and Vascular Biology</i> and <i>Circulation</i>, as of query in 2021. Predefined variables including experimental conditions, intervention, and outcomes were extracted from each publication to produce a preclinical atherosclerosis database.</p><p><strong>Results: </strong>Extracted data include animal sex, diet, intervention type, and distinct plaque pathologies (size, inflammation, and lipid content). Procedures are provided to standardize data extraction, attribute interventions to specific genes, and transform the database for use with available transcriptomics software. The database integrates hundreds of genes, each directly tested in vivo for causation in a murine atherosclerosis model. The database is provided to allow the research community to perform integrated analyses that reflect the global impact of decades of atherosclerosis investigation.</p><p><strong>Conclusions: </strong>This database is provided as a resource for future interrogation of sub-data sets associated with distinct plaque pathologies, cell type, or sex. We also provide the methods and software needed to expand this data set and apply this approach to the extensive repository of peer-reviewed data utilizing preclinical models to interrogate mechanisms of diverse human diseases.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004397"},"PeriodicalIF":6.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11021141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140334912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}