Circulation: Genomic and Precision Medicine最新文献

{"title":"Association of Pathogenic/Likely Pathogenic Genetic Variants for Cardiomyopathies With Clinical Outcomes: A Multiancestry Analysis in the All of Us Research Program.","authors":"Naman S Shetty, Akhil Pampana, Mokshad Gaonkar, Nirav Patel, Nehal Vekariya, J Gustav Smith, Rajat Kalra, C Anwar A Chahal, Christopher Semsarian, Peng Li, Garima Arora, Pankaj Arora","doi":"10.1161/CIRCGEN.124.005113","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.005113","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to evaluate the prevalence of pathogenic/likely pathogenic cardiomyopathy variant carriers in a multiancestry US population and examine the risk of adverse clinical outcomes.</p><p><strong>Methods: </strong>This retrospective cohort study included multiancestry US adults aged ≥18 years with sequencing data from the All of Us Research Program. Pathogenic/likely pathogenic variants in cardiomyopathy genes were identified using the ClinVar database. The primary outcome was heart failure. Secondary outcomes included cardiomyopathy and arrhythmia. Outcomes were identified from electronic health records. Interval-censored Cox models, taking age on the timescale, were used to assess the risk of outcomes in pathogenic/likely pathogenic variant carriers with noncarriers as the reference group.</p><p><strong>Results: </strong>Among 167 435 individuals (median age, 55.2 [39.5-66.3] years; 61.7% female; 40.7% non-European ancestry) included, the proportion of pathogenic/likely pathogenic cardiomyopathy variant carriers was 0.7% of the overall population and 0.8%, 0.8%, 0.5%, and 1.2% of European, African, East Asian, and South Asian ancestry individuals, respectively. Over the lifetime, there were 12 867 heart failure events (205 in carriers and 12 662 in noncarriers), with an incidence rate of 3.05 (95% CI, 2.66-3.49) per 1000 person-years in carriers and 1.37 (95% CI, 1.35-1.40) in noncarriers (HR_adj, 2.30 [95% CI, 2.04-2.60]). Cardiomyopathy occurred in 5164 (161 in carriers and 5003 in noncarriers), with an incidence rate of 2.38 (95% CI, 2.04-2.78) per 1000 person-years among carriers and 0.54 (95% CI, 0.53-0.56) in noncarriers (HR_adj, 4.31 [95% CI, 3.73-4.97]). There were 19 405 arrhythmia events (263 in carriers and 19 142 in noncarriers), with an incidence rate of 3.93 (95% CI, 3.48-4.44) per 1000 person-years among carriers and 2.09 (95% CI, 2.06-2.12) in noncarriers (HR_adj, 2.12 [95% CI, 1.78-2.53]).</p><p><strong>Conclusions: </strong>Pathogenic/likely pathogenic cardiomyopathy variant carriers have an increased risk of heart failure, cardiomyopathy, and arrhythmias. Despite the modest overall prevalence, the associated risks suggest potential benefits of targeted genetic screening for early detection and management.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005113"},"PeriodicalIF":6.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157161","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":"Identification and Functional Assessment of Candidate Causal <i>Cis</i>-Regulatory Variants Underlying Electrocardiographic QT Interval GWAS Loci.","authors":"Supraja Kadagandla, Lavanya Gunamalai, Dongwon Lee, Ashish Kapoor","doi":"10.1161/CIRCGEN.124.005032","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.005032","url":null,"abstract":"<p><strong>Background: </strong>Identifying causal variants among tens or hundreds of associated variants at each locus in genome-wide association studies (GWAS) is challenging. As the vast majority of GWAS variants are noncoding, sequence variation at <i>cis</i>-regulatory elements (CREs) affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following this hypothesis, combined with the observation that open chromatin is a universal hallmark of all types of CREs, we aimed to identify candidate causal <i>cis</i>-regulatory variants underlying QT interval GWAS loci.</p><p><strong>Methods: </strong>Common variants in high linkage disequilibrium with genome-wide significant variants were identified using variant call format tools. Genome-wide maps of cardiac putative CREs were generated by MACS2-based peak calling in human cardiac left ventricular DNase I sequencing and Assay for Transposase-Accessible Chromatin using sequencing data sets (<i>n</i>=13). Variant-CRE overlap was performed using custom tracks in the Table Browser tool at the UCSC Genome Browser. Luciferase reporter-based enhancer assays for variant-centered test elements were performed in mouse HL1 cardiomyocyte cells. Reporter activities of allelic pairs were compared using a Student <i>t</i> test.</p><p><strong>Results: </strong>At a dozen GWAS loci, selected for higher effect sizes and better understanding of the likely causal genes, we identified all genome-wide significant variants (<i>n</i>=1401) and included all common variants (minor allele frequency >1%) in high linkage disequilibrium (<i>r</i>²>0.9) with them as candidate variants (<i>n</i>=3482). Candidate variants were filtered for overlap with cardiac left ventricular putative CREs to identify candidate causal <i>cis</i>-regulatory variants (<i>n</i>=476), which were further assessed for being a known cardiac expression quantitative trait locus variant as additional functional evidence (<i>n</i>=243). Functional evaluation of a subset of seven candidate variants by luciferase reporter-based enhancer assays in HL1 cells using variant-centered test elements led to the identification of 6 enhancer variants with significant allelic differences.</p><p><strong>Conclusions: </strong>These efforts have generated a comprehensive set of candidate causal variants expected to be enriched for <i>cis</i>-regulatory potential and thereby, explaining the observed genetic associations.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005032"},"PeriodicalIF":6.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149503","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":"Development and Validation of Polygenic Risk Scores for Blood Pressure Traits in Continental African Populations.","authors":"Ebuka Onyenobi, Michael Zhong, Opeyemi Soremekun, Abram Kamiza, Romuald Boua, Tinashe Chikwore, Segun Fatumo, Ananyo Choudhury, Scott Hazelhurst, Clement Adebamowo, Michele Ramsay, Bamidele Tayo, Jennifer S Albrecht, Timothy D O'Connor, Yuji Zhang, Braxton D Mitchell, Sally N Adebamowo","doi":"10.1161/CIRCGEN.124.005048","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.005048","url":null,"abstract":"<p><strong>Background: </strong>Most polygenic risk scores (PRS) have been developed in European populations, frequently leading to limited transferability across diverse ancestry populations. This study aimed to develop and evaluate PRS for blood pressure (BP) traits in continental African (African) populations and investigate how African genetic diversity influences PRS performance.</p><p><strong>Methods: </strong>We generated PRS for systolic BP, diastolic BP, pulse pressure, and hypertension. We used a pan-African cohort as the target population and compared singleancestry and multiancestry PRS methods. We compared the performance of African ancestry-derived PRS against multiancestry PRS on the entire data set and within South, East, and West African subpopulations.</p><p><strong>Results: </strong>Multiancestry PRS demonstrated significantly higher predictive accuracy compared with singleancestry PRS models. PRS predictive accuracy varied across different African regions, with the highest performance observed in East Africa. In the combined population, the difference in mean BP values between the first multiancestry PRS quartile and the top quartile was 6.53 (95% CI, 5.3-7.74), 3.81 (95% CI, 3.9-4.52), and 3.59 (95% CI, 2.4-4.32) mm Hg for systolic BP, diastolic BP, and pulse pressure, respectively. Individuals in the highest PRS risk quartile had odds of hypertension that were 1.47 (95% CI, 1.7-1.69) times greater than those in the lowest risk quartile.</p><p><strong>Conclusions: </strong>These findings highlight the importance of integrating diverse ancestries in PRS development and accounting for subpopulation genetic variation to improve the predictive accuracy of BP PRS in African populations.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005048"},"PeriodicalIF":6.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149501","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":"Thoracic Aortic Disease in Patients With Heterozygous Variants Outside the Central Region of <i>FBN2</i>.","authors":"Till Joscha Demal, Marco Sachse, Celia Metzlaff, Helke Schüler, Katalin Szöcs, Jakob Olfe, Veronika Stark, Peter Frommolt, Yskert von Kodolitsch, Thomas S Mir, Meike Rybczynski, Hermann Reichenspurner, Kerstin Kutsche, Christian Kubisch, Christian Detter, Georg Rosenberger","doi":"10.1161/CIRCGEN.124.004672","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004672","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous pathogenic variants in the central region (exon 23-34) of <i>FBN2</i> cause a hereditary connective tissue disorder named congenital contractural arachnodactyly, which presents with obligatory skeletal features but rarely with vascular manifestations. Scarce data exist on the association between <i>FBN2</i> variants and aortic disease. This study aimed to investigate whether the location of <i>FBN2</i> variants correlates with distinct clinical features, including aortic disease.</p><p><strong>Methods: </strong>In this case-controlled cohort study, we ascertained clinical features, sequenced 62 (candidate) disease genes, and classified variants according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines in 392 patients with suspected connective tissue or thoracic aortic diseases. We summarized our results and published data and compared clinical manifestations between patients with variants outside and within the central region of <i>FBN2</i>.</p><p><strong>Results: </strong>Heterozygous <i>FBN2</i> variants outside the central region were identified in 10 patients from 5 families. Two variants were of uncertain significance, 1 was likely pathogenic, and 2 were pathogenic. A total of 60% of these patients had thoracic aortic disease, but only 20% were diagnosed with congenital contractural arachnodactyly according to an established clinical scoring system. Combined data from the literature and this study revealed that patients with <i>FBN2</i> variants outside the central region presented with aortic dilatation (55.0% versus 9.9%; <i>P</i><0.001) more often and had less pronounced musculoskeletal manifestations (congenital contractural arachnodactyly score, 5.6±5.1 versus 9.8±3.6; <i>P</i>=0.011) compared with those with central region variants.</p><p><strong>Conclusions: </strong>Our results suggest that heterozygous <i>FBN2</i> variants outside the central region predispose individuals to thoracic aortic disease and are less associated with the typical clinical presentation of congenital contractural arachnodactyly than pathogenic variants in the <i>FBN2</i> central region.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004672"},"PeriodicalIF":6.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126908","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":"Data Interoperability and Harmonization in Cardiovascular Genomic and Precision Medicine.","authors":"C Anwar A Chahal, Fares Alahdab, Babken Asatryan, Daniel Addison, Nay Aung, Mina K Chung, Spiros Denaxas, Jessilyn Dunn, Jennifer L Hall, Nathalie Pamir, David J Slotwiner, Jose D Vargas, Antonis A Armoundas","doi":"10.1161/CIRCGEN.124.004624","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004624","url":null,"abstract":"<p><p>Despite advances in cardiovascular care and improved outcomes, fragmented healthcare systems, nonequitable access to health care, and nonuniform and unbiased collection and access to healthcare data have exacerbated disparities in healthcare provision and further delayed the technological-enabled implementation of precision medicine. Precision medicine relies on a foundation of accurate and valid omics and phenomics that can be harnessed at scale from electronic health records. Big data approaches in noncardiovascular healthcare domains have helped improve efficiency and expedite the development of novel therapeutics; therefore, applying such an approach to cardiovascular precision medicine is an opportunity to further advance the field. Several endeavors, including the American Heart Association Precision Medicine platform and public-private partnerships (such as BigData@Heart in Europe), as well as cloud-based platforms, such as Terra used for the National Institutes of Health All of Us, are attempting to temporally and ontologically harmonize data. This state-of-the-art review summarizes best practices used in cardiovascular genomic and precision medicine and provides recommendations for systems' requirements that could enhance and accelerate the integration of these platforms.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004624"},"PeriodicalIF":6.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982592","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":"Phenotypic Diversity Caused by the <i>DES</i> Missense Mutation p.R127P (c.380G>C) Contributing to Significant Cardiac Mortality and Morbidity Associated With a Desmin Filament Assembly Defect.","authors":"Mohammad A Ebrahim, Naser M Ali, Buthaina Y Albash, Ali H Al Sayegh, Noof B Ahmad, Sabrina Voß, Franziska Klag, Joline Groß, Stephanie Holler, Volker Walhorn, Dario Anselmetti, Hendrik Milting, Andreas Brodehl","doi":"10.1161/CIRCGEN.124.004896","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004896","url":null,"abstract":"<p><strong>Background: </strong>Nonischemic cardiomyopathies are frequently caused by genetic mutations in about 100 different genes. The cardiomyopathy-associated gene <i>DES</i> encodes the intermediate filament protein desmin, which is important for the structural integrity of the cardiomyocytes.</p><p><strong>Methods: </strong>Using a next-generation sequencing approach, we performed cascade screening of a previously identified heterozygous <i>DES</i> missense mutation (c.380G>C, p.R127P) segregating in a large 6-generation Kuwaiti family, where several members died from sudden cardiac death or developed different cardiomyopathies, partially in combination with conduction disease and atrial fibrillation. <i>DES</i>-p.R127P affects a highly conserved position and is absent or super rare in different genetic human population databases. In silico predictions support the pathogenicity of <i>DES</i>-p.R127P. To investigate the detrimental impact of desmin-p.R127P, we performed cell transfection experiments using different cell lines and cardiomyocytes derived from induced pluripotent stem cells in combination with confocal microscopy.</p><p><strong>Results: </strong>These experiments demonstrated a severe desmin filament assembly defect leading to aberrant cytoplasmic desmin aggregates, even when co-expressed with wild-type desmin. Atomic force microscopy analysis supported the filament assembly defect of mutant recombinant desmin-p.R127P. To investigate the physicochemical impact of the amino acid at this position, we generated a set of 20 different variants and analyzed their filament formation in cell culture. Most of these variants disturbed the filament assembly comparable to p.R127P.</p><p><strong>Conclusions: </strong>In summary, we present and characterize a likely pathogenic missense mutation <i>DES</i>-p.R127P, which causes high cardiac mortality and morbidity in the described family. Our study has relevance for the interpretation and classification of further <i>DES</i> variants and might be helpful for the genetic counseling of patients and their relatives in future cases.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004896"},"PeriodicalIF":6.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986706","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":"Dissecting the Genetic Architecture of Intracranial Aneurysms.","authors":"Shaunak S Adkar, Julie Lynch, Ryan B Choi, Tanmoy Roychowdhury, Renae L Judy, Kaavya Paruchuri, Dong-Chuan Go, Sharika Bamezai, John Cabot, Sabina Sorondo, Michael G Levin, Dianna M Milewicz, Cristen J Willer, Pradeep Natarajan, Saiju Pyarajan, Kyong-Mi Chang, Scott Damrauer, Phil Tsao, Stephen Skirboll, Nicholas J Leeper, Derek Klarin","doi":"10.1161/CIRCGEN.123.004626","DOIUrl":"https://doi.org/10.1161/CIRCGEN.123.004626","url":null,"abstract":"<p><strong>Background: </strong>The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.</p><p><strong>Methods: </strong>We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.</p><p><strong>Results: </strong>We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; <i>P</i>=8.8×10^-¹⁷), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; <i>P</i>=1.2×10^-³), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; <i>P</i>=1.0×10^-⁴) ancestries.</p><p><strong>Conclusions: </strong>Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004626"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978923","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 Validity of Autosomal Dominant <i>ALPK3</i> Loss-of-Function Variants as a Cause of Hypertrophic Cardiomyopathy.","authors":"Sophie Hespe, Emma S Singer, Chloe Reuter, Brittney Murray, Elizabeth Jordan, Jessica Chowns, Stacey Peters, Megan Mayers, Belinda Gray, Ray E Hershberger, Anjali Owens, Christopher Semsarian, Amber Waddell, Babken Asatryan, Emma Owens, Courtney Thaxton, Mhy-Lanie Adduru, Kailyn Anderson, Emily E Brown, Lily Hoffman-Andrews, Fergus Stafford, Richard D Bagnall, Lucas Bronicki, Bert Callewaert, C Anwar A Chahal, Cynthia A James, Olga Jarinova, Andrew P Landstrom, Elizabeth M McNally, Laura Muiño-Mosquera, Victoria Parikh, Roddy Walsh, Bess Wayburn, James S Ware, Benjamin L Parker, Enzo R Porrello, David A Elliott, James W McNamara, Jodie Ingles","doi":"10.1161/CIRCGEN.124.004976","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004976","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004976"},"PeriodicalIF":6.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955187","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":"Diagnostic MicroRNA Signatures to Support Classification of Pulmonary Hypertension.","authors":"Niamh Errington, Li Zhou, Christopher J Rhodes, Yiu-Lian Fong, Lihan Zhou, Sokratis Kariotis, Eileen Harder, Aaron Waxman, Timothy Jatkoe, John Wharton, A A Roger Thompson, Robin Condliffe, David G Kiely, Luke S Howard, Mark Toshner, Cheng He, Dennis Wang, Martin R Wilkins, Allan Lawrie","doi":"10.1161/CIRCGEN.124.004862","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004862","url":null,"abstract":"<p><strong>Background: </strong>Patients with pulmonary hypertension (PH) are classified based on disease etiology and hemodynamic drivers. Classification informs treatment. The heart failure biomarker NT-proBNP (N-terminal pro-B-type natriuretic peptide) is used to help inform risk but is not specific to PH or sub-classification groups. There are currently no other biomarkers in clinical use to help guide diagnosis or risk.</p><p><strong>Methods: </strong>We profiled a retrospective cohort of 1150 patients from 3 expert centers with PH and 334 non-PH symptomatic controls (disease controls) from the United Kingdom to measure circulating levels of 650 microRNAs (miRNAs) in serum. NT-proBNP (ELISA) and 326 well-detected miRNAs (polymerase chain reaction) were prioritized by feature selection using multiple machine learning models. From the selected miRNAs, generalized linear models were used to describe miRNA signatures to differentiate PH and pulmonary arterial hypertension from the disease controls, and pulmonary arterial hypertension, PH due to left heart disease, PH due to lung disease, and chronic thromboembolic pulmonary hypertension from other forms of PH. These signatures were validated on a UK test cohort and independently validated in the prospective CIPHER study (A Prospective, Multicenter, Noninterventional Study for the Identification of Biomarker Signatures for the Early Detection of Pulmonary Hypertension) comprising 349 patients with PH and 93 disease controls.</p><p><strong>Results: </strong>NT-proBNP achieved a balanced accuracy of 0.74 and 0.75 at identifying PH and pulmonary arterial hypertension from disease controls with a threshold of 254 and 362 pg/mL, respectively but was unable to sub-categorize PH subgroups. In the UK cohort, miRNA signatures performed similarly to NT-proBNP in distinguishing PH (area under the curve of 0.7 versus 0.78), and pulmonary arterial hypertension (area under the curve of 0.73 versus 0.79) from disease controls. MicroRNA signatures outperformed NT-proBNP in distinguishing PH classification groups. External testing in the CIPHER cohort demonstrated that miRNA signatures, in conjunction with NT-proBNP, age, and sex, performed better than either NT-proBNP or miRNAs alone in sub-classifying PH.</p><p><strong>Conclusions: </strong>We suggest a threshold for NT-proBNP to identify patients with a high probability of PH, and the subsequent use of circulating miRNA signatures to help differentiate PH subgroups.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004862"},"PeriodicalIF":6.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980793","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":"Deletion of Exon 51 in a Humanized Duchenne Muscular Dystrophy Mouse Model Abolishes Ventricular Arrhythmia Predisposition.","authors":"Robin M Perelli, Madeleine J Sitton, Joel D Bohning, Adrian Pickar-Oliver, K Tyler McCullough, Mary E Moya-Mendez, Scott Zheng, Heather Daniels, Garth Devlin, Aravind Asokan, Charles A Gersbach, Andrew P Landstrom","doi":"10.1161/CIRCGEN.124.004867","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.004867","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004867"},"PeriodicalIF":6.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968189","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}