Circulation: Genomic and Precision Medicine最新文献

{"title":"Structural Evaluation of <i>RYR2</i>-CPVT Missense Variants and Continuous Bayesian Estimates of Their Penetrance.","authors":"Kundivy Dauda, Kohei Yamauchi, Matthew Ku, Devyn W Mitchell, Alex Shen, Loren Vanags, Jeffrey Schmeckpeper, Prince J Kannankeril, Bjorn C Knollmann, Matthew J O'Neill, Brett M Kroncke","doi":"10.1161/CIRCGEN.125.005457","DOIUrl":"10.1161/CIRCGEN.125.005457","url":null,"abstract":"<p><strong>Background: </strong>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is strongly associated with rare missense variants in <i>RYR2</i>, the gene encoding the intracellular calcium release channel RyR2.</p><p><strong>Methods: </strong>We curated 179 articles reviewed by 3 individuals to extrapolate <i>RYR2</i>-CPVT missense variant genotype-phenotype relationships. Purportedly neutral control variants were ascertained from <i>RYR2</i> missense variants observed in gnomAD and ClinVar. We performed an <i>RYR2</i>-CPVT Bayesian penetrance analysis by conditioning a CPVT penetrance prior (hereafter called Bayesian CPVT-prior) on variant-specific features (in silico and structural) calibrated by heterozygote phenotypes. We evaluated various features, including the Bayesian CPVT-prior, ClinVar, REVEL, and AlphaMissense against our observed CPVT penetrance, using Spearman rank-order correlations and Brier Scores. Penetrance estimates were superimposed on a cryo-EM structure of RyR2 to investigate hot-spot heterogeneity.</p><p><strong>Results: </strong>From the literature, we identified 1014 affected missense <i>RYR2</i> heterozygotes (468 unique variants), and further supplemented by purpuroted unaffected heterozygotes in GnomAD to a total of 622 575 heterozygotes (5181 unique variants). Among the predictors, the Bayesian CPVT-prior score had the highest Spearman rank-order and lowest Brier scores, respectively (0.19; 0.0090), compared with ClinVar (0.083; 0.019), REVEL (0.16; 0.018), or AlphaMissense (0.18; 0.018). Penetrance estimates for all <i>RYR2</i> missense variants are prospectively hosted at the Variant Browser website.</p><p><strong>Conclusions: </strong>Traditional categorical variant annotations limit accurate disease risk assessment, especially in populations unascertained for disease. A probabilistic, population-calibrated penetrance framework enables more meaningful prospective variant interpretation. Our Bayesian CPVT-prior outperforms current tools in evaluating RYR2 variant penetrance. We provide prospective Bayesian CPVT penetrance values for 29 242 RYR2 missense variants at our online variant browser.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005457"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519959","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":"Twenty-Five-Year Follow-Up of the MDDC1 Family: A <i>LMNA</i> Gene Variant Associated With Dilated Cardiomyopathy With Variable Skeletal Muscle Involvement.","authors":"Teresa Maria Capovilla, Manuela Iseppi, Salvatore Distaso, Marta Gigli, Matteo Dal Ferro, Michele Moretti, Annamaria Iorio, Antonella Mancinelli, Marco Merlo, Luisa Mestroni, Alessia Paldino, Gianfranco Sinagra","doi":"10.1161/CIRCGEN.125.005528","DOIUrl":"10.1161/CIRCGEN.125.005528","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005528"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590361","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":"Phenome-Wide Mendelian Randomization Identifying Circulating Proteins for Cardiovascular Traits in Populations of African Ancestry.","authors":"Susannah Selber-Hnatiw, Katerina Trajanoska, Justin Pelletier, Chen-Yang Su, Peyton McClelland, Daniel Taliun, Satoshi Yoshiji, Vincent Mooser, Claude Bhérer, Sirui Zhou","doi":"10.1161/CIRCGEN.125.005159","DOIUrl":"10.1161/CIRCGEN.125.005159","url":null,"abstract":"<p><strong>Background: </strong>Circulating proteins represent robust drug targets with therapeutic potential. Many discoveries have focused on European-ancestry populations, disregarding minuscule yet substantial proteomic differences that may contribute to disease and alter drug generalizability in other ancestry groups.</p><p><strong>Methods: </strong>Using 2-sample Mendelian randomization and colocalization, we analyzed the effects of 1562 circulating proteins on 145 cardiometabolic-centric outcomes to identify robust protein-phenotype associations in African-ancestry populations and reveal African-ancestry associations with heterogeneous effects. We further replicated these findings using the proteomic data available from the UK Biobank Pharma Proteomics Project and tested the effect of protein quantity in association with select phenotypes. Population branch statistics were also constructed to examine whether protein-genetic instruments under natural selection could lead to significant protein-outcome associations specific to the African ancestry.</p><p><strong>Results: </strong>We identified 115 robust protein target-outcome associations in African-ancestry populations. Among these, 51 demonstrated heterogeneous effects between African- and European-ancestry populations. We further replicated 4 cross-platform African-ancestry associations in the UK Biobank Pharma Proteomics Project and also revealed 4 significant, direct associations between protein levels and phenotypes. Ultimately, based on our prioritization criteria, we found that CD36 (glycoprotein IIIb), APOC1 (apolipoprotein C1), GSTA1 (glutathione S-transferase alpha 1), and FOLH1 (folate hydrolase 1) were shown to influence lipids and heart diseases, and were uniquely represented in African-ancestry populations. In addition, using population branch statistics, we showed that 47.5% of the 115 significant protein-outcome associations were possibly driven by <i>cis</i>-acting protein quantitative trait loci under natural selection.</p><p><strong>Conclusions: </strong>Multiple lines of evidence were used to interrogate proteomic determinants of cardiometabolic diseases and traits in African-ancestry populations. We highlighted actionable circulating protein targets that could represent potential drug targets for cardiovascular diseases specific to populations with African ancestry.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005159"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141316","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":"<i>ROBO2</i> Variants Associated With Atrial Septal Defect Define a Novel Regulatory Element.","authors":"Seong Won Kim, Michael Parfenov, Laura Rodriguez-Murillo, David A Conner, Arun Sharma, Inga Peter, Feng Xiao, Olivia Layton, Angela Tai, Tarsha Ward, Lauren K Wasson, Joshua M Gorham, Erica Mazaika, Valentina N Lagomarsino, Tracy L Young-Pearse, Elizabeth Goldmuntz, Hiroko Wakimoto, A J Agopian, David M McKean, Steven R DePalma, William T Pu, Christine E Seidman, Bruce D Gelb, Jonathan G Seidman","doi":"10.1161/CIRCGEN.124.004918","DOIUrl":"10.1161/CIRCGEN.124.004918","url":null,"abstract":"<p><strong>Background: </strong>Atrial septal defects (ASDs) are a prevalent type of congenital heart disease. Previous GWAS (Genome-Wide Association Studies) have identified common variants associated with ASDs, though their mechanisms remain unknown. We aimed to expand insights into the architecture of common variants associated with ASD risk and elucidate functional mechanisms.</p><p><strong>Methods: </strong>We conducted a GWAS using isolated ASD cases and healthy controls and replicated findings in an independent cohort. We examined epigenetic marks within this ASD locus in human induced pluripotent stem cell-derived cardiomyocytes and fetal human hearts. We characterized the consequences of deletions introduced by CRISPR-Cas9 mutagenesis of human induced pluripotent stem cells to assess the effect on downstream gene expression. In addition, we investigated the 3-dimensional genome architecture of the locus using chromosome conformation capture sequencing.</p><p><strong>Results: </strong>We identified a novel ASD locus on chromosome 3p12.3 encompassing the <i>ROBO2</i> gene, which encodes the Roundabout guidance receptor 2 for Slit ligands. This locus includes 15 common single nucleotide polymorphisms, an enhancer, and a CCCTC-binding factor (CTCF)-binding site. Deletions of varying lengths within the ASD-associated locus in human induced pluripotent stem cell-derived cardiomyocytes reduced <i>ROBO2</i> expression and dysregulated the expression of extracellular matrix genes. Chromosome conformation capture sequencing indicated that this region physically interacts with the <i>ROBO2</i> promoter and demonstrates that the CTCF-binding site is essential for this contact.</p><p><strong>Conclusions: </strong>Novel common single nucleotide polymorphisms in regulatory elements controlling <i>ROBO2</i> transcription contribute to risk for ASDs. These data infer key roles for the Roundabout guidance receptor 2 and Slit ligands in embryogenic development and maturation of the atrial septa.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004918"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13034621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200286","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":"Friend of GATA2 Variant Ser657Gly Is Associated With Coronary Microvascular Disease.","authors":"Marie A Guerraty, Shefali S Verma, Yi-An Ko, Michael A McQuillan, Donna M Conlon, John W Tobias, Michael G Levin, William Haury, Fangyuan Zheng, Tess Cherlin, Chao Zhang, Renae Judy, Sarah A Tishkoff, Scott M Damrauer, Zoltan Arany, Daniel J Rader","doi":"10.1161/CIRCGEN.125.005342","DOIUrl":"10.1161/CIRCGEN.125.005342","url":null,"abstract":"<p><strong>Background: </strong>The coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. FOG2 (friend of GATA 2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice. Little is known about the role of FOG2 in humans or its role in CMVD. Here, we report a genotype-first approach to determine the role of FOG2 in human CMVD.</p><p><strong>Methods: </strong>We performed phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants. We interrogated MagNET heart tissue data to identify genes and pathways associated with rs28374544. We then overexpressed FOG2S657G in a cardiomyocyte cell line and assessed the effects on cardiac metabolism and paracrine angiogenic signaling.</p><p><strong>Results: </strong>We identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Using phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants, we identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Individuals carrying the S657G variant, almost all of African ancestry, had increased chest pain, a smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic data sets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the HIF (hypoxia-inducible factor) pathway. In vitro functional studies show that compared with the FOG2 wild-type protein, the FOG2^S657G variant protein promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate.</p><p><strong>Conclusions: </strong>A common functional coding variant in FOG2, S657G, is associated with CMVD in humans. Altered angiogenic gene expression, regulated in part by FOG2, may contribute to CMVD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005342"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590363","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":"Associations of the <i>ICAM1</i> p.K56M HFpEF Risk Variant With Pericardial Adiposity and the Inflammatory Proteome.","authors":"Anushree Aneja, Kasen L Culler, Jingzhong Ding, Kent D Taylor, Sanjiv J Shah, Laura Rasmussen-Torvik, Ravi B Patel","doi":"10.1161/CIRCGEN.125.005475","DOIUrl":"10.1161/CIRCGEN.125.005475","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005475"},"PeriodicalIF":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13078727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626412","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":"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":5.5,"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":5.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":5.5,"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":5.5,"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}