Circulation: Genomic and Precision Medicine最新文献

{"title":"Relationships of Circulating Plasma Metabolites With the QT Interval in a Large Population Cohort.","authors":"William J Young, Mihir M Sanghvi, Julia Ramírez, Michele Orini, Stefan van Duijvenboden, Helen R Warren, Andrew Tinker, Pier D Lambiase, Patricia B Munroe","doi":"10.1161/CIRCGEN.124.004978","DOIUrl":"10.1161/CIRCGEN.124.004978","url":null,"abstract":"<p><strong>Background: </strong>There is a higher prevalence of heart rate corrected QT (QTc) prolongation in patients with diabetes and metabolic syndrome. QT interval genome-wide association studies have identified candidate genes for cardiac energy metabolism, and experimental studies suggest that polyunsaturated fatty acids have direct effects on ion channel function. Despite this, there has been limited study of metabolite concentration relationships with QT intervals.</p><p><strong>Methods: </strong>In 21 056 UK Biobank participants with same-day electrocardiograms and plasma profiling of 100 metabolites, per-metabolite regression analyses with the QTc were performed adjusting for clinically relevant variables. Participants with ischemic heart disease or heart failure were excluded. Significant metabolites (<i>P</i><5×10^-4) that replicated in an independent UK Biobank sample (N=5304), underwent Least Absolute Shrinkage and Selection Operator regression with clinical variables to identify top predictors and calculate the QTc variance explained. Two-sample Mendelian randomization and locus-level colocalization analyses were performed to test for causal relationships and shared genetic etiologies, respectively.</p><p><strong>Results: </strong>Twenty-two metabolites were associated with the QTc in main and replication regression analyses, including ketone bodies, fatty acids, glycolysis-related molecules, and amino acids. Top associations were 3-hydroxybutyrate (8.9 ms), acetone (7.9 ms), and polyunsaturated fatty acids (-7.3 ms), when comparing the highest versus lowest deciles. A combined metabolite and clinical variables Least Absolute Shrinkage and Selection Operator model significantly increased the QTc variance explained compared with the clinical-only model (11.2% versus 7.7%; <i>P</i>=0.002). There was support for a causal relationship between Linoleic acid to fatty acid ratio and the QTc, and evidence for colocalization for 15 metabolites at 7 QT loci, including <i>CASR</i> for citrate and glutamine.</p><p><strong>Conclusions: </strong>In the largest study of metabolite-QTc relationships, we identify 22 associated metabolites and clinically relevant effect sizes, with evidence for genetic support. For the first time, we report a potentially protective effect of polyunsaturated fatty acids in humans. These metabolites may be risk factors in acquired and congenital long-QT syndrome and warrant additional investigation for arrhythmia risk stratification.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004978"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032890","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":"Age-Dependent Contributions of Rare and Common Genetic Variation in Atrial Fibrillation.","authors":"Zhanlin Chen, Peter F Aziz, Philip Greenland, Rod Passman, Adam S Gordon, Gregory Webster","doi":"10.1161/CIRCGEN.124.004958","DOIUrl":"10.1161/CIRCGEN.124.004958","url":null,"abstract":"<p><strong>Background: </strong>Genetic variation contributes to atrial fibrillation (AF), but its impact may vary with age. The <i>All of Us</i> Research Program contains whole-genome sequencing of data from 100 574 adult participants with linked electronic health records.</p><p><strong>Methods: </strong>We assessed clinical, monogenic, and polygenic associations with AF in a cross-sectional analysis, stratified by age: <45 years (n=22 290), 45 to 60 years (n=26 805), and >60 years (n=51 659). AF was defined as ≥2 Systematized Nomenclature of Medicine-Clinical Terms codes on separate days. We identified pathogenic/likely pathogenic variants in 145 cardiac genes with dominant inheritance and calculated a previously established polygenic risk score. Adjusted for known clinical factors, multivariable analysis quantified associations between monogenic and polygenic factors and AF in each age group.</p><p><strong>Results: </strong>Among 100 574 participants (mean age 59±16 years), 7811 (7.8%) had AF, while 92 763 (92%) did not. Monogenic pathogenic/likely pathogenic variants were associated with AF across all age groups, most strongly in participants aged <45 years (odds ratio, 2.1 [95% CI, 1.2-3.2]; <i>P</i>=0.007). In contrast, the polygenic risk score was not associated with AF in this youngest group (odds ratio, 1.0 [95% CI, 0.9-1.2]; <i>P</i>=0.650) but was in older groups (odds ratio 1.3 [95% CI, 1.2-1.4]; <i>P</i><0.001 for both ages 45-60 and >60 years). Clinical factors were significantly associated with AF (C-index, 0.84 [0.83-0.84]; <i>P</i><0.001), with marginal improvement when monogenic and polygenic data were added (C-index, 0.86 [0.86-0.87]; <i>P</i><0.001). In hazard-based time-to-event analysis, monogenic variants were associated with earlier onset, whereas the polygenic risk score was not associated with age of onset.</p><p><strong>Conclusions: </strong>In this large cross-sectional study, monogenic variants were associated with AF throughout life, particularly in younger participants, whereas polygenic risk was associated with AF only in older participants. While genetic information added only marginal improvements to AF risk discrimination beyond existing clinical risk factors, monogenic variants were associated with an earlier age of onset in participants with AF.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004958"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032909","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":"Preintervention Intake of Whole Grains Versus Refined Grains, and the Gut Microbiome, Discriminate the Antihypertensive Effect of Prebiotic Fiber.","authors":"Matthew Snelson, Dakota Rhys-Jones, Hamdi A Jama, Darren J Creek, Charles R Mackay, Jane Muir, Francine Z Marques","doi":"10.1161/CIRCGEN.124.005019","DOIUrl":"10.1161/CIRCGEN.124.005019","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005019"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945263","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":"Novel <i>Cardiac Troponin-I</i> Missense Variant (c.593C>T) Is Associated With Familial Hypertrophic Cardiomyopathy in Golden Retrievers.","authors":"Victor N Rivas, Dayna A Goldsmith, Michael W Vandewege, Ronald H L Li, Sandra M Losa, Meghan Leber, Panchan Sitthicharoenchai, Kim Hawkes, Jennifer L Davies, Carolyn Legge, Sarah Revell, Joshua A Stern","doi":"10.1161/CIRCGEN.125.005096","DOIUrl":"10.1161/CIRCGEN.125.005096","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is a naturally occurring cardiac disorder afflicting humans, cats, rhesus macaques, pigs, and rarely dogs. The disease is characterized by maladaptive left ventricular wall thickening. Over 1500 sarcomere-coding mutations explain HCM in humans, whereas only 3 have been reported in cat breeds. To date, no mutations have been described in dogs. HCM in a nuclear family of Golden Retrievers was identified following the sudden cardiac death of 3 related puppies <2 years of age from 2 dam-offspring repeat matings.</p><p><strong>Methods: </strong>Whole-genome sequencing on the 3 affected puppies, along with nuclear family members (ie, sire, dam, 4 unaffected littermates, 4 unaffected half-siblings), and 1 distantly related, geriatric, cardiovascularly normal Golden Retriever was performed (n=14). Candidate variant genotyping was performed in an unphenotyped cohort of dogs (n=2771) and an expanded population of phenotyped, unrelated Golden Retrievers (n=45). Left ventricular tissue immunofluorescence staining was subsequently performed to investigate incorporation and expression of mutant protein within the cardiac sarcomere of HCM-affected cases.</p><p><strong>Results: </strong>Gross and histopathologic evaluations of the HCM-affected puppies revealed hallmark features of the disease, including cardiomyocyte hypertrophy, interstitial fibrosis, and left-sided congestive heart failure. Segregation analysis of called variants, performed under assumptions of an autosomal-recessive mode of inheritance, identified a single segregating c.593C>T missense variant in <i>TNNI3</i> (<i>Cardiac Troponin-I</i>). This variant was not observed in the unphenotyped (n=2771) nor in the phenotyped, unrelated cohort of dogs (n=45). Immunofluorescence staining of left ventricular tissues did not reveal obvious aberrant protein localization and expression at the sarcomeric level, suggesting the molecular pathogenesis of the <i>TNNI3</i> variant is not related to abnormal protein incorporation within the sarcomere.</p><p><strong>Conclusions: </strong>This variant represents the first-ever reported HCM-associated variant in any canine species, and its identification holds promise for establishing translational models, genetic screening, and early disease prevention within the breed.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005096"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945274","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":"Long-Term Arrhythmic Outcomes of KCNJ2 Variant Carriers in Japan.","authors":"Koichi Kato, Yosuke Higo, Takanori Aizawa, Megumi Fukuyama, Keiko Sonoda, Takashi Hisamatsu, Yusuke Fujii, Hideki Itoh, Takeru Makiyama, Seiko Ohno, Yoshihisa Nakagawa, Minoru Horie","doi":"10.1161/CIRCGEN.125.005188","DOIUrl":"10.1161/CIRCGEN.125.005188","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005188"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191332","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":"Lung Single-Cell Transcriptomics Reveal Diverging Pathobiology and Opportunities for Precision Targeting in Scleroderma-Associated Versus Idiopathic Pulmonary Arterial Hypertension.","authors":"Tijana Tuhy, Julie C Coursen, Tammy Graves, Michael Patatanian, Christopher Cherry, Shannon E Niedermeyer, Sarah L Khan, Darin T Rosen, Michael P Croglio, Mohab Elnashar, Todd M Kolb, Stephen C Mathai, Rachel L Damico, Paul M Hassoun, Larissa A Shimoda, Karthik Suresh, Micheala A Aldred, Catherine E Simpson","doi":"10.1161/CIRCGEN.124.004936","DOIUrl":"10.1161/CIRCGEN.124.004936","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide, endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH). We hypothesized that distinct and overlapping gene expression patterns in SSc-PAH versus IPAH lung tissues could inform the investigation of precision-targeted therapies.</p><p><strong>Methods: </strong>Lung tissue samples from 4 SSc-PAH, 4 IPAH, and 4 failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative lung tissue bank. Single-cell RNA sequencing was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis, transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map.</p><p><strong>Results: </strong>SSc-PAH samples showed a higher proportion of fibroblasts compared with failed donors and a higher proportion of dendritic cells/macrophages compared with IPAH. Gene set enrichment analysis revealed enriched pathways related to epithelial-to-mesenchymal transition, apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial-to-endothelial cell signaling observed. Macrophage-to-endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures.</p><p><strong>Conclusions: </strong>Overlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve outcomes in patient with SSc-PAH. Future studies should validate these targets and explore their therapeutic efficacy.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004936"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674009","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":"Correction of the Murine Model of Congenital Heart Disease Associated With the <i>Nkx2-5</i> Mutation Using Prime Editing.","authors":"Toshiyuki Ko, Daigo Nishijo, Atsumi Tsuji-Hosokawa, Iku Tsuchiya, Seitaro Nomura, Bo Zhang, Yue Jiang, Kaho Fujimori, Takashi Hiruma, Ryo Abe, Takahiro Jimba, Shunsuke Inoue, Zhehao Dai, Manami Katoh, Mikako Katagiri, Masamichi Ito, Hiroyuki Morita, Shuji Takada, Norihiko Takeda, Akihiro Umezawa, Issei Komuro","doi":"10.1161/CIRCGEN.124.005194","DOIUrl":"10.1161/CIRCGEN.124.005194","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005194"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246682","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":"Plasma Proteomics Reveals Dysregulated Pathways Across the Spectrum <i>LMNA</i> Cardiomyopathy.","authors":"Usman A Tahir, Daniel Reichart, Anisha Purohit, Jacob L Barber, Gaurav Tiwari, Laurie Farrell, Julia E Marine, Darius Roy, Joshen Patel, Catherine G Ireland, Carolyn Y Ho, Christine E Seidman, Robert E Gerszten, Neal K Lakdawala","doi":"10.1161/CIRCGEN.124.004924","DOIUrl":"10.1161/CIRCGEN.124.004924","url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in the <i>lamin A/C</i> (<i>LMNA</i>) gene cause an aggressive form of dilated cardiomyopathy (DCM), marked by higher rates of advanced conduction disease, malignant ventricular tachyarrhythmias, and advanced heart failure compared with other causes of nonischemic cardiomyopathy. However, the mechanisms that drive the development and progression of <i>LMNA</i> DCM are incompletely understood.</p><p><strong>Methods: </strong>To identify proteins and biological pathways associated with likely pathogenic/pathogenic <i>LMNA</i> variants, we measured ≈3000 plasma proteins using the OLINK platform in a genetic DCM cohort consisting of <i>LMNA</i> (n=41) and sarcomeric (n=18) DCM, along with phenotype-negative individuals from family-based cascade screening (n=55) with (<i>LMNA</i>, n=16; sarcomere, n=12) or without the family variant (genotype negative, n=27).</p><p><strong>Results: </strong>We identified several novel proteins associated with <i>LMNA</i> DCM compared with sarcomeric DCM, including EDA2R (ectodysplasin A2 receptor; per log2 fold change in relative protein abundance, β=3.0; <i>P</i>=4×10^-³) and <i>MYL4</i> (myosin light chain 4; β=2.32; <i>P</i>=5×10^-³). Among the proteins associated with <i>LMNA</i> DCM, 26 showed concordant differential gene expression from single-cell sequencing in cardiomyocytes from myocardial biopsies in advanced <i>LMNA</i> heart failure compared with control hearts (false discovery rate, <5%). We performed principal component analyses on these 26 proteins to identify proteomic signatures of <i>LMNA</i> DCM and found the first principal component to be associated with left ventricular ejection fraction and complete heart block in the <i>LMNA</i> DCM cohort. Six proteins-EDA2R, MYL4, CRIM1 (cysteine-rich transmembrane bone morphogenetic protein regulator 1), TPR (translocated promoter region), FSTL3 (follistatin-like 3), and NFYA (nuclear transcription factor Y)-were associated with <i>LMNA</i> pathogenic variants across phenotype-negative individuals, DCM, and their respective cardiomyocyte RNA expression profiles in advanced heart failure.</p><p><strong>Conclusions: </strong>Proteomic profiling in individuals with likely pathogenic/pathogenic <i>LMNA</i> variants illuminated integral pathways across the spectrum of <i>LMNA</i> DCM. These findings may help advance genotype-driven biomarker discovery and tailored therapeutic development in <i>LMNA</i> DCM.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004924"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282639","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":"Correction to: 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 Chikowore, Segun Fatumo, Ananyo Choudhury, Scott Hazelhurst, Clement Adebamowo, Michèle Ramsay, Bamidele Tayo, Jennifer S Albrecht, Timothy D O'Connor, Yuji Zhang, Braxton D Mitchell, Sally N Adebamowo","doi":"10.1161/HCG.0000000000000099","DOIUrl":"10.1161/HCG.0000000000000099","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e000099"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741329","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":"Machine Learning-Based Plasma Protein Risk Score Improves Atrial Fibrillation Prediction Over Clinical and Genomic Models.","authors":"Min Seo Kim, Shaan Khurshid, Shinwan Kany, Lu-Chen Weng, Sarah Urbut, Carolina Roselli, Leonoor F J M Wijdeveld, Sean J Jurgens, Joel T Rämö, Patrick T Ellinor, Akl C Fahed","doi":"10.1161/CIRCGEN.124.004943","DOIUrl":"10.1161/CIRCGEN.124.004943","url":null,"abstract":"<p><strong>Background: </strong>Clinical factors discriminate incident atrial fibrillation (AF) risk with moderate accuracy, with only modest improvement after incorporation of polygenic risk scores. Whether emerging large-scale proteomic profiling can augment AF risk estimation is unknown.</p><p><strong>Methods: </strong>In the UK Biobank cohort, we derived and validated a machine learning model to predict incident AF risk using serum proteins (Pro-AF). We compared Pro-AF to a validated clinical risk score (Cohorts for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation, CHARGE-AF) and an AF polygenic risk score. Models were evaluated in a multiply resampled test set from nested cross-validation (internal test set), and a sample of UK Biobank participants separate from model development (hold-out test set). Metrics included discrimination of 5-year incident AF using time-dependent area under the receiver operating characteristic curve and net reclassification.</p><p><strong>Results: </strong>Trained in 32 631 UK Biobank participants, Pro-AF predicts incident AF using 121 protein levels (out of 2911 protein analytes). When assessed in the internal test set comprising 30 632 individuals (mean age 57±8 years, 54% women, 2045 AF events) and hold-out test set comprising 13 998 individuals (mean age 57±8 years, 54% women, 870 AF events), discrimination of 5-year incident AF was highest using Pro-AF (area under the receiver operating characteristic curve internal: 0.761 [95% CI, 0.745-0.780], hold-out: 0.763 [0.734-0.784]), followed by CHARGE-AF (0.719 [0.700-0.737]; 0.702 [0.668-0.730]) and the polygenic risk score (0.686 [0.668-0.702]; 0.682 [0.660-0.710]). AF risk estimates were well-calibrated, and the addition of Pro-AF led to substantial continuous net reclassification improvement over CHARGE-AF (eg, internal test set 0.410 [0.330-0.492]). A simplified Pro-AF including only the 5 most influential proteins (NT-proBNP [N-terminal pro-brain natriuretic peptide], EDA2R [ectodysplasin A2 receptor], NPPB [B-type natriuretic peptide], BCAN [brevican core protein], and GDF15 [growth/differentiation factor 15]), retained favorable discriminative value (area under the receiver operating characteristic curve internal: 0.750 [0.733-0.768]; hold-out: 0.759 [0.732-0.790]).</p><p><strong>Conclusions: </strong>A machine learning-based protein score discriminates 5-year incident AF risk favorably compared with clinical and genetic risk factors. Large-scale proteomic analysis may assist in the prioritization of individuals at risk for AF for screening and related preventive interventions.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004943"},"PeriodicalIF":5.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309596","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}