Circulation: Genomic and Precision Medicine最新文献

{"title":"Circulating Cardiovascular Proteomic Associations With Genetics and Disease.","authors":"Kathryn A McGurk, Lara Curran, Arunashis Sau, Fu Siong Ng, Brian Halliday, James S Ware, Declan P O'Regan","doi":"10.1161/CIRCGEN.124.005005","DOIUrl":"https://doi.org/10.1161/CIRCGEN.124.005005","url":null,"abstract":"<p><strong>Background: </strong>The analysis of the circulating proteome can identify translational modifiers and biomarkers of disease expressivity and severity at a given time point. Here, we explore the relationships between protein measures implicated in cardiovascular disease and whether they mediate causal relationships between cardiovascular risk factors and disease development.</p><p><strong>Methods: </strong>To understand the relationships between circulating biomarkers and genetic variants, medications, anthropometric traits, lifestyle factors, imaging-derived measures, and diagnoses of cardiovascular disease, we undertook in-depth analyses of measures of 9 plasma proteins with a priori roles in genetic and structural cardiovascular disease or treatment pathways (ACE2 [angiotensin-converting enzyme 2], ACTA2 [actin alpha 2], ACTN4 [actinin alpha 4], BAG3 [BAG cochaperone 3], BNP [B-type natriuretic peptide], CDKN1A [cyclin-dependent kinase inhibitor 1A], NOTCH1 [neurogenic locus notch homolog protein 1], NT-proBNP [N-terminal pro-B-type natriuretic peptide], and TNNI3 [troponin I]) from the Pharma Proteomics Project of the UK Biobank cohort (over 45 000 participants sampled at recruitment).</p><p><strong>Results: </strong>We identified significant variability in circulating proteins with age, sex, ancestry, alcohol intake, smoking, and medication intake. Phenome-wide association studies highlighted the range of cardiovascular clinical features with relationships to protein levels. Genome-wide genetic association studies identified variants near <i>GCKR</i>, <i>APOE</i>, and <i>SERPINA1</i>, that modified multiple circulating protein levels (BAG3, CDKN1A, and NOTCH1). NT-proBNP and BNP levels associated with variants in <i>BAG3</i>. ACE2 levels were increased with a diagnosis of hypertension or diabetes, particularly in females, and were influenced by variants in genes associated with diabetes (<i>HNF1A</i> and <i>HNF4A</i>). Two-sample Mendelian randomization identified ACE2 as protective for systolic blood pressure and type-2 diabetes.</p><p><strong>Conclusions: </strong>From a panel of circulating proteins, the results from this observational study provide evidence that ACE2 is causally protective for hypertension and diabetes. This suggests that ACE2 treatment may provide additional protection from these cardiovascular diseases. This study provides an improved understanding of the circulating pathways depicting cardiovascular disease dynamics.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005005"},"PeriodicalIF":5.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238285","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":"Fibroblasts Are the Primary Contributors to a Disrupted Micro-Environment in End-Stage Pediatric Hypertrophic Cardiomyopathy.","authors":"Hanna J Tadros, Diwakar Turaga, Yi Zhao, Chang-Ru Tsai, Iki A Adachi, Xiao Li, James F Martin","doi":"10.1161/CIRCGEN.125.005192","DOIUrl":"https://doi.org/10.1161/CIRCGEN.125.005192","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) is a relatively rare but debilitating diagnosis in the pediatric population, and patients with end-stage HCM require heart transplantation. Here, we have examined the transcriptome in ventricular tissue from this patient group to identify cell states and underlying cellular processes unique to pediatric HCM.</p><p><strong>Methods: </strong>We performed single-nucleus RNA sequencing on explanted hearts at transplant in 3 pediatric patients with end-stage HCM and compared findings to pediatric control and adult HCM.</p><p><strong>Results: </strong>We identified distinct underlying cellular processes in cardiomyocytes, fibroblasts, endothelial cells, and myeloid cells compared with controls. Pediatric HCM was enriched in cardiomyocytes exhibiting stressed myocardium gene signatures and underlying pathways associated with cardiac hypertrophy; cardiac fibroblasts exhibited activation signatures and compared with adult patients, exhibited heightened downstream processes associated with fibrosis and a unique, myofibroblast-like cluster with increased metabolic stress and antiapoptotic properties. We noted depletion of tissue-resident macrophages and increased vascular remodeling in endothelial cells in pediatric HCM.</p><p><strong>Conclusions: </strong>Our analysis provides the first single-nucleus analysis focused on end-stage pediatric HCM. Fibroblast-mediated cellular processes were the most prominent in pediatric HCM, which had more downstream processes associated with fibrosis than did adult HCM.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005192"},"PeriodicalIF":5.5,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231540","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":"Large-Scale Proteomics-Based Risk Score for the Prediction of Incident Cardio-Kidney-Metabolic Disease Risk.","authors":"Adithya K Yadalam, Chang Liu, Qin Hui, Alexander C Razavi, Laurence S Sperling, Arshed A Quyyumi, Yan V Sun","doi":"10.1161/CIRCGEN.124.005125","DOIUrl":"10.1161/CIRCGEN.124.005125","url":null,"abstract":"<p><strong>Background: </strong>Cardio-kidney-metabolic (CKM) disease represents a significant public health challenge. While proteomics-based risk scores (ProtRS) enhance cardiovascular risk prediction, their utility in improving risk prediction for a composite CKM outcome beyond traditional risk factors remains unknown.</p><p><strong>Methods: </strong>We analyzed 23 815 UK Biobank participants without baseline CKM disease, defined by <i>International Classification of Diseases</i>-Tenth Revision codes as cardiovascular disease (coronary artery disease, heart failure, stroke, peripheral arterial disease, atrial fibrillation/flutter), kidney disease (chronic kidney disease or end-stage renal disease), or metabolic disease (type 2 diabetes or obesity). The sample was randomly divided into ProtRS training (70%, n=16 671) and validation (30%, n=7144) cohorts. A least absolute shrinkage and selection operator-based Cox regression model of 2913 Olink-based proteins was utilized to develop the ProtRS in the training cohort. We then assessed the association of the ProtRS with incident CKM disease risk in the validation cohort with competing-risk regression after adjusting for traditional risk factors and evaluated its ability to discriminate incident CKM disease risk with C-indices.</p><p><strong>Results: </strong>The study sample had a mean age of 56.1 years; 44% were men, and 94% were White. Over a median follow-up of 13.5 years, 3235 and 1407 incident CKM disease events occurred in the training and validation cohorts, respectively. A ProtRS based on the weighted sum of the 238 least absolute shrinkage and selection operator-selected proteins was significantly associated with incident CKM disease risk (subdistribution hazard ratio per 1-SD, 1.87 [95% CI, 1.73-2.03]; <i>P</i><0.001) in the validation cohort after adjustment for traditional risk factors. The addition of the ProtRS to a traditional risk factor model significantly improved incident CKM disease risk discrimination beyond the traditional risk factor model (C-index, 0.73 [0.72-0.74] versus 0.71 [0.69-0.72]; ΔC-index, 0.03 [0.02-0.04]).</p><p><strong>Conclusions: </strong>A ProtRS was independently associated with incident CKM disease risk and improved risk prediction beyond traditional risk factors in a population free of CKM disease at baseline.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005125"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032824","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":"Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in <i>ENG</i> and <i>ACVRL1</i>.","authors":"Anthony R Anzell, Carter M White, Brenda Diergaarde, Jenna C Carlson, Beth L Roman","doi":"10.1161/CIRCGEN.124.005061","DOIUrl":"10.1161/CIRCGEN.124.005061","url":null,"abstract":"<p><strong>Background: </strong>Hereditary hemorrhagic telangiectasia (HHT) is a near-fully penetrant autosomal dominant disorder characterized by nosebleeds, anemia, and arteriovenous malformations. The great majority of HHT cases are caused by heterozygous loss-of-function mutations in <i>ACVRL1</i> or <i>ENG</i>, which encode proteins that function in bone morphogenetic protein signaling. HHT prevalence is estimated at 1 in 5000 and is accordingly classified as rare. However, HHT is suspected to be underdiagnosed.</p><p><strong>Methods: </strong>To estimate the true prevalence of HHT, we summed allele frequencies of predicted pathogenic variants in <i>ACVRL1</i> and <i>ENG</i> using 3 methods. For method 1, we included Genome Aggregation Database (gnomAD v4.1) variants with ClinVar annotations of pathogenic or likely pathogenic, plus unannotated variants with a high probability of causing disease. For method 2, we evaluated all <i>ACVRL1</i> and <i>ENG</i> gnomAD variants using threshold filters based on accessible in silico pathogenicity prediction algorithms. For method 3, we developed a machine learning-based classification system to improve the classification of missense variants.</p><p><strong>Results: </strong>We calculated an HHT prevalence of between 2.1 in 5000 and 11.9 in 5000, or 2 to 12× higher than current estimates. Application of our machine learning-based classification method revealed missense variants as the greatest contributor to pathogenic allele frequency and similar HHT prevalence across genetic ancestries.</p><p><strong>Conclusions: </strong>Our results support the notion that HHT is underdiagnosed and that HHT prevalence may be above the threshold of a rare disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005061"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079791","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>CARS2</i> Hypermethylation Is a Risk Factor for Heart Failure: A Project Baseline Health Substudy.","authors":"Jessica A Regan, Jordan Franklin, Kalyani Kottilil, Nicholas Cauwenberghs, Kenneth W Mahaffey, Pamela S Douglas, Fatima Rodriguez, Francois Haddad, Adrian F Hernandez, Svati H Shah, Lydia Coulter Kwee","doi":"10.1161/CIRCGEN.125.005073","DOIUrl":"10.1161/CIRCGEN.125.005073","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005073"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12521830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231581","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":"Digging Deeper Into Cardiovascular Plasma Proteomics: Opportunities and Limitations of Current Platforms.","authors":"Pich Chhay, Owen Tang, Lizhuo Ai, Stuart J Cordwell, Michael P Gray, Jean Y H Yang, Jennifer E Van Eyk, Peter J Psaltis, Gemma A Figtree","doi":"10.1161/CIRCGEN.125.005198","DOIUrl":"10.1161/CIRCGEN.125.005198","url":null,"abstract":"<p><p>Coronary artery disease remains the leading cause of death worldwide. One of the greatest developments in preventive cardiology has been the identification and treatment of standard modifiable risk factors associated with coronary artery disease. However, despite advances in the management of standard modifiable risk factors, there is an escalating number of patients who continue to present with acute coronary syndromes, a trend that is particularly concerning given the decreasing age-adjusted incidence rates of these conditions. This persistent clinical challenge underscores the urgency to explore alternative approaches for early detection and improved risk stratification. In recent years, the emergence of proteomics technologies has brought forth promising avenues for the discovery of novel biomarkers that hold the potential to revolutionize the timely detection and management of coronary artery disease. Proteomics enables the high throughput and often unbiased analysis of protein abundance, modifications, and interactions within pathways relevant to cardiovascular disease pathogenesis. Of particular importance is the capability to detect low-abundance proteins including those with currently unknown functions. While the functional assessment of these proteins aligns more with mechanistic studies, their role in biomarker discovery is equally important. Such detection may provide new insights into cardiac pathophysiology, including potential new markers for early disease detection and risk assessment. Although the latest proteomics technology and bioinformatic approaches do provide the opportunity for novel discoveries, understanding the limitations of each technology platform is important. This review provides an updated overview of major proteomic platforms and discusses their methodological strengths, constraints, and applications, using recent coronary artery disease studies as illustrative examples. By integrating proteomics data with clinical information, including advanced noninvasive imaging techniques and other omics disciplines, such as genomics and metabolomics, we can deepen our understanding of disease mechanisms and improve risk stratification. Although the discovery of novel biomarkers represents a significant step forward in the field, their true clinical value is contingent upon their rigorous validation in clinical trials and implementation studies. With our current capabilities and emerging advancements, we are well-positioned to advance proteomics-guided precision medicine in cardiovascular care over the coming decade.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005198"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231533","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":"Drug Target Mendelian Randomization: Distinguishing Between Causal Mechanisms and Biomarkers of Those Mechanisms.","authors":"Jonathan L Ciofani, Daniel Han, Ravinay Bhindi","doi":"10.1161/CIRCGEN.125.005336","DOIUrl":"10.1161/CIRCGEN.125.005336","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005336"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882259","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 Variants Associated With Congenital Heart Disease: A Meta-Analysis of Ethnicity and Subtype-Specific Susceptibility.","authors":"Hae Sung Chon, Ji Wan Park","doi":"10.1161/CIRCGEN.124.005039","DOIUrl":"10.1161/CIRCGEN.124.005039","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is the most common heterogeneous birth defect, with prevalence varying across populations. A comprehensive meta-analysis could refine the genetic risk estimates and enhance our understanding of CHD susceptibility.</p><p><strong>Methods: </strong>We conducted a meta-analysis of 175 case-control studies investigating 107 genetic variants across 72 gene regions. Pooled odds ratios were calculated using 6 genetic models, with subgroup analyses by ethnicity and CHD subtype. Gene Ontology and network analyses elucidated the functional significance of implicated genes.</p><p><strong>Results: </strong>Thirty-six variants were significantly associated with CHD (<i>P</i><0.05), including 7 missense mutations in <i>NRP1</i>, <i>MTHFR</i>, <i>MTRR</i>, <i>NOS3</i>, and <i>DNMT1</i>. Ten variants, including rs1531070 in <i>MAML3</i> (odds ratio, 1.52; <i>P</i>=5.9×10^-15), surpassed genome-wide significance. Ethnicity-specific analyses identified 13 significant variants, including <i>MTHFR</i>-rs1801131 in Chinese (<i>P</i>=1.71×10^-10), <i>STX18-AS1</i>-rs870142 in Europeans (<i>P</i>=7.13×10^-16), and <i>MTRR</i>-rs1801394 in Middle Eastern populations (<i>P</i>=9.8×10^-8). Subtype analyses revealed 25 variants associated with specific CHD subtypes, such as <i>STX18-AS1</i>-rs16835979 with atrial septal defect (<i>P</i>=2.1×10^-16) and variants in <i>MTHFR</i>, <i>NRP1</i>, and <i>PTPN11</i> with tetralogy of Fallot (<i>P</i>=3.0×10^-17-2.33×10^-10). The rs1801133 variant was linked to double-outlet right ventricle (<i>P</i>=3.0×10^-11) and patent ductus arteriosus (<i>P</i>=6.5×10^-9). Gene Ontology and network analyses highlighted genes involved in cardiac development and folate metabolism in CHD pathogenesis.</p><p><strong>Conclusions: </strong>This meta-analysis refines CHD risk estimates across diverse ancestries and subtypes, underscoring the complex genetic architecture of the disease. Variants involved in cardiac development and metabolic pathways represent promising targets for precision medicine in CHD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005039"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945223","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":"New Genetic Loci Implicated in Cardiac Morphology and Function Using Three-Dimensional Population Phenotyping.","authors":"Chang Lu, Kathryn A McGurk, Sean L Zheng, Antonio de Marvao, Paolo Inglese, Wenjia Bai, James S Ware, Declan P O'Regan","doi":"10.1161/CIRCGEN.124.005116","DOIUrl":"10.1161/CIRCGEN.124.005116","url":null,"abstract":"<p><strong>Background: </strong>Cardiac remodeling occurs in the mature heart and is a cascade of adaptations in response to stress, which are primed in early life. A key question remains as to the processes that regulate the geometry and motion of the heart and how it adapts to stress.</p><p><strong>Methods: </strong>We performed spatially resolved phenotyping using machine learning-based analysis of cardiac magnetic resonance imaging in 47 549 UK Biobank participants. We analyzed 16 left ventricular spatial phenotypes, including regional myocardial wall thickness and systolic strain in both circumferential and radial directions. In up to 40 058 participants, genetic associations across the allele frequency spectrum were assessed using genome-wide association studies with imputed genotype participants, and exome-wide association studies and gene-based burden tests using whole-exome sequencing data. We integrated transcriptomic data from the GTEx project and used pathway enrichment analyses to further interpret the biological relevance of identified loci. To investigate causal relationships, we conducted Mendelian randomization analyses to evaluate the effects of blood pressure on regional cardiac traits and the effects of these traits on cardiomyopathy risk.</p><p><strong>Results: </strong>We found 42 loci associated with cardiac structure and contractility, many of which reveal patterns of spatial organization in the heart. Whole-exome sequencing revealed 3 additional variants not captured by the genome-wide association study, including a missense variant in <i>CSRP3</i> (minor allele frequency 0.5%). The majority of newly discovered loci are found in cardiomyopathy-associated genes, suggesting that they regulate spatially distinct patterns of remodeling in the left ventricle in an adult population. Our causal analysis also found regional modulation of blood pressure on cardiac wall thickness and strain.</p><p><strong>Conclusions: </strong>These findings provide a comprehensive description of the pathways that orchestrate heart development and cardiac remodeling. These data highlight the role that cardiomyopathy-associated genes have on the regulation of spatial adaptations in those without known disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005116"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7618224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238319","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":"Observational and Experimental Evidence on the Interaction Between Fine Particulate Matter and Shared Genetic Variants Across Atherosclerotic Cardiovascular Disease Subtypes.","authors":"Jingyi Zhang, Shanshan Ran, Lan Chen, Miao Cai, Fei Tian, Baozhuo Ai, Samantha E Qian, Maya Tabet, Steven W Howard, Yin Yang, Hualiang Lin","doi":"10.1161/CIRCGEN.124.004986","DOIUrl":"10.1161/CIRCGEN.124.004986","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have suggested that the associations between ambient air pollution and atherosclerotic cardiovascular diseases (ASCVD) differ by genotype. A genome-wide approach provides a more comprehensive understanding of this relationship on a genomic scale.</p><p><strong>Methods: </strong>Using data from ≈300 000 UK Biobank participants, we conducted a genome-wide interaction analysis on 10 745 802 variants. We examined the interactions between fine particulate matter (PM_2.5) and genetic variants across 3 ASCVD subtypes: coronary artery disease, ischemic stroke, and peripheral artery disease. A polygenic risk score was constructed, and functional annotation identified potential genes at loci interacting with air pollution. In vivo studies explored how genome-wide interaction analysis-identified genes interacting with PM_2.5 might contribute to atherosclerotic plaque progression.</p><p><strong>Results: </strong>During 12.55 years of follow-up, 42 696 ASCVD events were observed. Genome-wide interaction analysis identified 12 loci shared across the ASCVD subtypes related to PM_2.5 exposure. Functional annotation suggested these loci and colocalized genes are involved in pathways such as cell-cell adhesion, deoxyribonucleotide biosynthesis, RNA metabolism, and calcium homeostasis. High genetic risk combined with PM_2.5 exposure was associated with coronary artery disease, ischemic stroke, and peripheral artery disease, with hazard ratios and 95% CIs of 1.35 (1.32-1.37), 1.53 (1.47-1.58), and 1.68 (1.62-1.75), respectively. Animal studies confirmed that adenosine kinase gene expression might interact with PM_2.5, potentially influencing atherosclerotic plaque development through inflammation.</p><p><strong>Conclusions: </strong>Our study identified genome-wide loci interacting with PM_2.5 and linked adenosine kinase expression in response to PM_2.5 exposure to the formation of atherosclerotic plaques, highlighting potential pathways that connect PM_2.5 to ASCVD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004986"},"PeriodicalIF":5.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032865","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}