Circulation: Genomic and Precision Medicine最新文献

{"title":"Assessing Genetic Testing in Adult Congenital Heart Disease: Current State and Patient Perspectives.","authors":"Angela Onorato, Kara Klinkebiel, Rachel Levenseller, Bimal P Chaudhari, Isaac Kistler, Kathryn Vannatta, Rachel Gosselin, Karen Texter, Vidu Garg, May Ling Mah","doi":"10.1161/CIRCGEN.125.005527","DOIUrl":"10.1161/CIRCGEN.125.005527","url":null,"abstract":"<p><strong>Background: </strong>Genetic variation affects clinical outcomes, prognosis, and family planning decisions in individuals with congenital heart disease (CHD). While genetic testing recommendations for infants and children with CHD have expanded, similar broad guidelines are lacking for patients with adult CHD (ACHD). Here, we investigated the current state of genetic testing in patients with ACHD and their perceptions toward testing, which has not been previously reported.</p><p><strong>Methods: </strong>A single-center prospective cohort survey of patients with ACHD aged ≥18 years was evaluated in a large ACHD clinic over a 12-month period.</p><p><strong>Results: </strong>Among 336 survey respondents (median age, 29 years; 52% male), CHD lesions were wide ranging, albeit largely represented by conotruncal (35%) or left ventricular outflow tract (35%) lesions. Most patients did not have children (64%) or a family history of CHD (79%). Thirteen percent had evidence of prior genetic testing despite 41% to 98% meeting criteria by current pediatric recommendations. Most desired genetic testing (68%) though interest varied by sex, education level, and family status. Individual and family health factors were reported as the most influential considerations for genetic testing.</p><p><strong>Conclusions: </strong>Few patients with ACHD have had genetic testing despite most being eligible based on current pediatric guidelines, likely related to birth era. Patients were interested in genetic testing though demographic factors and family status affected interest. The lack of broad recommendations for genetic testing in the ACHD population likely represents a significant barrier to increased utilization of genetic tests.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005527"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149339","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":"Angiographic Burden of Coronary Atherosclerosis Partially Mediates the Association Between ASCVD Risk Factors and Outcomes.","authors":"Noah L Tsao, Sarah A Abramowitz, Gabrielle E Shakt, Renae Judy, Austin T Hilliard, Scott M Damrauer, Themistocles L Assimes, Shoa L Clarke, Catherine Tcheandjieu, Michael G Levin","doi":"10.1161/CIRCGEN.125.005266","DOIUrl":"10.1161/CIRCGEN.125.005266","url":null,"abstract":"<p><strong>Background: </strong>Coronary artery disease (CAD) is a major contributor to cardiovascular morbidity (including myocardial infarction and heart failure) and mortality. Although the burden of CAD (number and degree of coronary artery stenosis) has been observationally linked to these outcomes, the causal contribution and independence from traditional cardiovascular risk factors have been poorly defined.</p><p><strong>Methods: </strong>We developed a polygenic risk score for angiographic CAD burden using data from the VA Million Veteran Program (n=41 507) and validated this score using data from the Penn Medicine Biobank (n=41 660 with genotyping, N=3771 with angiogram data). We then used publicly available GWAS data and a mediation framework using Mendelian Randomization to investigate whether angiographic CAD burden contributes to adverse cardiovascular outcomes independent of traditional risk factors.</p><p><strong>Results: </strong>We first demonstrated that increasing levels of the polygenic risk score were strongly associated with increased prevalence of nonobstructive and obstructive CAD on coronary angiography (odds ratio, 1.26 [95% CI, 1.14-1.39]; odds ratio, 2.23 [95% CI, 1.94-2.55], respectively) and was associated with other forms of cardiometabolic disease including peripheral artery disease and atherosclerotic risk factors including hyperlipidemia, hypercholesterolemia and hypertension. Through Mendelian randomization analyses, we found that lipid measures (apolipoprotein B, high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides) and type 2 diabetes significantly influenced myocardial infarction risk through their effects on angiographic CAD burden. Furthermore, low-density lipoprotein and total cholesterol demonstrated significant indirect effects on heart failure through angiographic CAD burden, suggesting these lipids primarily influence heart failure through their impact on coronary atherosclerosis.</p><p><strong>Conclusions: </strong>Our findings indicate that angiographic burden of coronary atherosclerosis mediates a substantial proportion of the relationship between traditional cardiovascular risk factors and adverse outcomes. These results support prioritizing primary prevention efforts targeting modifiable risk factors to prevent the development and progression of coronary plaques before clinical disease manifestation.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005266"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13266589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225801","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":"Cardiovascular Morbidity and Mortality in Fabry Disease.","authors":"Emanuele Monda, Athanasios Bakalakos, Annamaria Del Franco, Rosa Lillo, Maria Chiara Meucci, Letizia Spinelli, Vanda Parisi, Maria Alessandra Schiavo, Marta Rubino, Francesca Graziani, Francesco Cappelli, Maurizio Pieroni, Antonio Pisani, Guido Iaccarino, Robin Lachmann, Elaine Murphy, Uma Ramaswami, Derralynn Hughes, Elena Biagini, Giuseppe Limongelli, Perry Mark Elliott","doi":"10.1161/CIRCGEN.125.005361","DOIUrl":"10.1161/CIRCGEN.125.005361","url":null,"abstract":"<p><strong>Background: </strong>Cardiac involvement is the main determinant of adverse outcomes in Fabry disease. The study aimed to investigate cardiovascular outcomes in patients with Fabry disease.</p><p><strong>Methods: </strong>This was a multicenter, retrospective, longitudinal study of consecutively referred adult patients with Fabry disease. The primary end point was the occurrence of major adverse cardiovascular events defined as a composite of cardiovascular death, major arrhythmic events, bradyarrhythmias requiring pacemaker implantation, and stroke.</p><p><strong>Results: </strong>A total of 680 patients (age, 42.3±15.9 years; 41.0% male; 68.7% on disease-specific therapy) were included. During a median follow-up of 7.1 (interquartile range, 3.9-11.6) years, 92 patients (13.5%) experienced a major adverse cardiovascular event. At 10 years, freedom from major adverse cardiovascular event was 85.1% (95% CI, 81.3-88.2) and was lower in men compared with women (76.1% [95% CI, 68.9-81.9] versus 91.3% [95% CI, 87.0-94.2]; log-rank χ²=26.9; <i>P</i><0.001). On multivariable analysis, age (hazard ratio, 1.04 [95% CI, 1.01-1.06] per 1 year; <i>P</i><0.001), estimated glomerular filtration rate (hazard ratio, 0.99 [95% CI, 0.98-0.99] per 1 mL/min per 1.73 m²; <i>P</i><0.001), QRS interval (hazard ratio, 1.02 [95% CI, 1.01-1.03] per 1 ms; <i>P</i>=0.002), and left ventricular mass index (hazard ratio, 1.01 [95% CI, 1.00-1.01] per 1 g/m²; <i>P</i>=0.032) were independent predictors of major adverse cardiovascular events during follow-up.</p><p><strong>Conclusions: </strong>This study shows that the prevention and treatment of cardiovascular disease remain an unmet need for patients with Fabry disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005361"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124090","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":"Multiomics for Risk Stratification in Atherosclerotic Cardiovascular Disease.","authors":"Liv Tybjærg Nordestgaard, Paolo Magni, Miron Sopić, Melody Chemaly, Ljubica Matic, Nawar Dalila, Fábio Trindade, Brooke N Wolford, Zulema Rodriguez-Hernandez, Núria Amigó, Alberico L Catapano, Lluìs Masana, Yvan Devaux","doi":"10.1161/CIRCGEN.125.005451","DOIUrl":"10.1161/CIRCGEN.125.005451","url":null,"abstract":"<p><p>Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide. Preventing ASCVD is of utmost importance; however, a large proportion of preventable cases is not discovered early enough to initiate relevant treatment. Risk stratification for ASCVD includes classical risk factors, such as sex, age, smoking habits, blood pressure, cholesterol levels, and diabetes. Current risk prediction models, including the Systematic Coronary Risk Evaluation 2 algorithms, are designed for individuals aged 40 to 69 years and relate to 10-year risk and not to lifetime risk, thereby being inaccurate for the young. Another problem is the underdiagnosis of events in women, thereby underestimating risk. Multiomics, encompassing genomics, epigenomics, transcriptomics, epitranscriptomics, proteomics, and metabolomics, offers new opportunities. Polygenic risk scores derived from genomic data may improve ASCVD risk classification. While genomic risk is established at inception, epigenomics captures the influence of environmental exposures over the lifespan through dynamic DNA modifications that regulate gene expression. Proteomics-based prediction reflects interactions between genetic inheritance, and modifiable and nonmodifiable influences. Transcriptomic analyses of carotid plaques have clustered human atherosclerotic lesions into distinct molecular subgroups, and changes in RNA methylation of circulating blood cells have been linked to clinical outcomes after ASCVD. Metabolomics identifies metabolic signatures, including lipid subclass alterations, amino acid imbalances, and inflammatory markers, all associated with cardiovascular disease incidence. In this review, we highlight current challenges, explore potential solutions, and discuss how integrating multiple omic layers through computational modeling (multiomics) could enhance patient stratification, optimize clinical management, and reduce the global burden of ASCVD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005451"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509987","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":"Editors and Editorial Board.","authors":"","doi":"10.1161/HCG.0000000000000100","DOIUrl":"https://doi.org/10.1161/HCG.0000000000000100","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":"19 1","pages":"e000100"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212394","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":"Genetic Association of Circulating Proteins and Gene Transcripts With Spontaneous Coronary Artery Dissection.","authors":"Maddalena Ardissino, Alec P Morley, Buu Truong, Art Schuermans, Rohin K Reddy, Martina Milani, Alice Sacco, James S Ware, Stephen Burgess, Brian P Halliday, Thong Huy Cao, Paulene A Quinn, Leong L Ng, Ania A Baranowska-Clarke, Pradeep Natarajan, Adam S Butterworth, Michael C Honigberg, Kypros Nicolaides, Thomas Webb, David Adlam, Antonio de Marvao","doi":"10.1161/CIRCGEN.125.005330","DOIUrl":"10.1161/CIRCGEN.125.005330","url":null,"abstract":"<p><strong>Background: </strong>Spontaneous coronary artery dissection (SCAD) is an uncommon cause of myocardial infarction that disproportionately affects women, particularly during pregnancy and the peripartum period. Limited understanding of its underlying pathophysiology hinders the development of effective preventive and therapeutic strategies.</p><p><strong>Methods: </strong>This study investigated associations between genetically predicted circulating proteins and tissue-specific RNA levels with genetically predicted SCAD risk using Mendelian randomization and Bayesian colocalization. Genetic scores for >1500 circulating proteins were derived from the UK Biobank (N=34 557) and deCODE (N=35 559). Scores for 13 848 gene transcripts in arterial and fibroblast tissues were generated from Genotype-Tissue Expression data. Associations between these scores and SCAD were assessed in a genome-wide association study meta-analysis of 1917 individuals with SCAD and 9292 controls. Findings were validated in vitro using mass spectrometry-based proteomic analysis of extracellular vesicles from 50 patients with SCAD and 50 healthy controls.</p><p><strong>Results: </strong>Genetic associations of 4 circulating proteins with SCAD (AFAP1 [actin filament-associated protein 1], ECM1 [extracellular matrix protein 1], SPON1 [spondin 1], and STAT6 [signal transducer and activator of transcription 6]) were identified. Two were supported by gene expression data (AFAP1 and ECM1), and one by tissue-specific Bayesian colocalization analyses (ECM1). Protein interaction mapping identified potential shared pathways through the JAK-STAT (Janus kinases and signal transducers and activators of transcription) signaling pathway and inflammatory regulation. Mass spectrometry-based proteomic analysis demonstrated that ECM1 was significantly upregulated in SCAD cases versus controls.</p><p><strong>Conclusions: </strong>Integrative analysis of proteomic, transcriptomic, and experimental data revealed 4 circulating proteins genetically associated with SCAD risk, with ECM1 emerging as a key protein with a likely causal role in SCAD pathogenesis. These findings highlight biological pathways for mechanistic studies and protein targets for potential therapeutic interventions.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":"19 1","pages":"e005330"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212354","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":"MEK Inhibition Improves Clinical Outcome in Premature Infants With Multisystemic <i>RASA1</i> Disease.","authors":"Elizabeth K Baker, Pavalan Selvam, Ryan Monsberger, Laura S Peterson, John Erickson, Vanina Taliercio, Jessica Hass Alfonso, Lonnie J Miner, David Viskochil, K Nicole Weaver","doi":"10.1161/CIRCGEN.125.005578","DOIUrl":"10.1161/CIRCGEN.125.005578","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005578"},"PeriodicalIF":5.5,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146060639","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":"Genetic Architecture of N-Terminal Pro-B-Type Natriuretic Peptide in a Multiancestry Study Population.","authors":"Naman S Shetty, Akhil Pampana, Mokshad Gaonkar, Amrita Nayak, Harshvir S Bal, Nirav Patel, Nehal Vekariya, J Gustav Smith, Alanna C Morrison, Bing Yu, Bruce M Psaty, Eric Boerwinkle, James S Floyd, Jerome I Rotter, Kent D Taylor, Leslie A Lange, Marguerite R Irvin, Mary Cushman, Stephen S Rich, Ramachandran S Vasan, Thomas J Wang, Xiuqing Guo, Peng Li, Garima Arora, Pankaj Arora","doi":"10.1161/CIRCGEN.124.005130","DOIUrl":"10.1161/CIRCGEN.124.005130","url":null,"abstract":"<p><strong>Background: </strong>NPs (natriuretic peptides) are bioactive hormones crucial for regulating blood pressure, glucose homeostasis, and lipid metabolism. Despite the high heritability of circulating NP levels, the genetic determinants of NP regulation, particularly across ancestries and sexes, remain poorly understood. The objective of the current study was to identify genetic variants associated with NT-proBNP (N-terminal pro-B-type NP) levels in a multiancestry study population.</p><p><strong>Methods: </strong>Whole genome sequencing and array-based data from 81 213 individuals without heart failure were analyzed from the Trans-Omics for Precision Medicine cohorts, UK Biobank, All of Us Research Program, and REGARDS (Reasons for Geographic and Racial Differences in Stroke) study to identify common, rare, and structural variants associated with NT-proBNP levels. The main outcome of the study was rank-based inverse normal and standardized NT-proBNP levels. Genetic associations with NT-proBNP were examined, followed by gene prioritization, transcriptome-wide association studies, colocalization, and rare variant analyses.</p><p><strong>Results: </strong>Nine novel loci and 3 previously reported loci were identified to be associated with NT-proBNP levels. Novel structural variants were detected across 12 loci. Similar effect sizes were observed for both common and rare variants. Key genes such as <i>BAG3</i> (10q26.11) and <i>SLC39A8</i> (4q24) were identified through gene prioritization, with prior animal models supporting their therapeutic relevance. Rare variant analysis identified 6 masks with significant associations, specifically non-coding masks, suggesting regulatory modulation of NT-proBNP.</p><p><strong>Conclusions: </strong>This study identifies novel common, rare, and structural variants associated with NT-proBNP levels, highlighting the contribution of both coding and regulatory non-coding variation. These findings advance our understanding of the genetic architecture of NT-proBNP and may inform future cardiometabolic therapeutic strategies.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005130"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13321388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146060735","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":"Gain-of-Function Variant <i>TRPC6 A404V</i> Is Associated With Doxorubicin-Related Cardiomyopathy.","authors":"Ying Wu, Xiaojing Sun, Ru-Xing Wang, Joseph S Reddy, Hon-Chi Lee, Nadine Norton, Tong Lu","doi":"10.1161/CIRCGEN.125.005334","DOIUrl":"10.1161/CIRCGEN.125.005334","url":null,"abstract":"<p><strong>Background: </strong>TRPC6 (transient receptor potential canonical 6) channels, encoded by the <i>TRPC6</i> gene, are widely expressed in cardiomyocytes and play a critical role in maintaining intracellular Ca²⁺ homeostasis. Variants in <i>TRPC6</i> are associated with chemotherapy-related cardiomyopathy. Specifically, the <i>TRPC6 A404V</i> polymorphism, with a minor (404 V) allele frequency of 12% in the general population, has been identified in patients undergoing anthracycline therapy. However, the underlying mechanisms remain largely unexplored.</p><p><strong>Methods: </strong>Using patch-clamp recordings, Ca²⁺ imaging, computational analysis, and molecular biology techniques, we assessed the effects of doxorubicin and its metabolite, doxorubicinol, on regulating TRPC6 alanine (A) at position 404 replaced by valine (V; A404V) channel expression and function in a heterologous expression system and native cardiac cells.</p><p><strong>Results: </strong>Both additive and recessive models demonstrated a significant association between the <i>TRPC6 A404V</i> variant and doxorubicin-related cardiomyopathy. The TRPC6 A404V channel exhibited higher membrane expression levels compared with the wild type (WT) control. Patch-clamp recordings showed that both TRPC6 WT and A404V channels remained mostly inactive at baseline. Application of 50 μmol/L 1-oleoyl acetyl-sn-glycerol (OAG), a TRPC6 activator, significantly increased the inward- and outward-current densities of WT and A404V channels. Furthermore, a 24-hour treatment with 0.5 μmol/L doxorubicin enhanced TRPC6 mRNA expression and potentiated the OAG effects on both WT and A404V channels, with a more pronounced response in A404V channels. Treatment with 0.5 μmol/L doxorubicinol had no effect on OAG-induced current densities in either WT or A404V channels. Doxorubicin effects on intracellular Ca²⁺ levels were confirmed by Ca²⁺ imaging in native cardiac cells. Computational modeling revealed that the A404V mutation induces a conformational change in the OAG-binding pocket, enhancing its interaction with OAG in the A404V protein compared with the WT control.</p><p><strong>Conclusions: </strong>The <i>TRPC6 A404V</i> is a gain-of-function variant that exhibits enhanced activity in the presence of doxorubicin. Therefore, the <i>TRPC6 A404V</i> variant represents a risk factor for anthracycline-induced cardiotoxicity in patients with cancer.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005334"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12914740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146060641","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":"Unbiased Characterization of Atrial Fibrillation Phenotypic Architecture Provides Insight Into Genetic Liability and Clinically Relevant Outcomes.","authors":"Giovanni Davogustto, Shilin Zhao, Yajing Li, Eric Farber-Eger, Brandon D Lowery, Lauren Lee Shaffer, Jonathan D Mosley, M Benjamin Shoemaker, Yaomin Xu, Dan M Roden, Quinn S Wells","doi":"10.1161/CIRCGEN.124.004853","DOIUrl":"10.1161/CIRCGEN.124.004853","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) is a common and clinically heterogeneous arrhythmia. Machine learning algorithms can define data-driven disease subtypes in an unbiased fashion, but whether these AF subgroups align with underlying mechanisms, such as polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear.</p><p><strong>Methods: </strong>We identified individuals with AF in a large biobank linked to electronic health records and genome-wide genotyping. We applied an unsupervised coclustering machine learning algorithm to 35 curated and uncorrelated clinical features to identify distinct phenotypic AF clusters. The clinical inflammatory status of the clusters was defined using measured biomarkers (CRP, ESR, WBC, Neutrophil %, Platelet count, RDW) within 6 months of first AF mention. Polygenic risk scores for AF and for cytokine levels were used to assess the genetic liability of clusters to AF and inflammation, respectively. Clinical outcomes were collected from electronic health records up to the last medical contact.</p><p><strong>Results: </strong>The analysis included 23 271 subjects with AF, of which 6023 had available genome-wide genotyping. The machine learning algorithm identified 3 phenotypic clusters that were distinguished by increasing prevalence of comorbidities, particularly renal disease and coronary artery disease. Polygenic liability to AF across clusters was highest in the low comorbidity cluster. Clinically measured inflammatory biomarkers were highest in the high comorbidity cluster. There was no difference between groups in genetically predicted levels of inflammatory biomarkers. Cluster assignment was associated with mortality, stroke, bleeding, and use of cardiac implantable electronic devices after AF diagnosis.</p><p><strong>Conclusions: </strong>Patients within AF subgroups identified by clustering were distinguished by comorbidity burden and associated with risk of clinically important outcomes, polygenic liability to AF, and clinical inflammation, but not with genetically predicted inflammatory cytokine levels. Our study empirically demonstrates the complementary roles of comorbidity and genetic liability as major drivers of AF phenotypic variability using hypothesis-free methods.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004853"},"PeriodicalIF":6.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12880694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146060637","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}