Circulation: Genomic and Precision Medicine最新文献

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Long-Term Arrhythmic Outcomes of KCNJ2 Variant Carriers in Japan. 日本KCNJ2变异携带者的长期心律失常结局
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-09-30 DOI: 10.1161/CIRCGEN.125.005188
Koichi Kato, Yosuke Higo, Takanori Aizawa, Megumi Fukuyama, Keiko Sonoda, Takashi Hisamatsu, Yusuke Fujii, Hideki Itoh, Takeru Makiyama, Seiko Ohno, Yoshihisa Nakagawa, Minoru Horie
{"title":"Long-Term Arrhythmic Outcomes of <i>KCNJ2</i> 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":"https://doi.org/10.1161/CIRCGEN.125.005188","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005188"},"PeriodicalIF":5.5,"publicationDate":"2025-09-30","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}
引用次数: 0
Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in ENG and ACVRL1. 从GnomAD等位基因频率计算出遗传性出血性毛细血管扩张症在ENG和ACVRL1中预测的致病变异。
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-09-18 DOI: 10.1161/CIRCGEN.124.005061
Anthony R Anzell, Carter White, Brenda Diergaarde, Jenna C Carlson, Beth L Roman
{"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 White, Brenda Diergaarde, Jenna C Carlson, Beth L Roman","doi":"10.1161/CIRCGEN.124.005061","DOIUrl":"https://doi.org/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":"2025-09-18","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}
引用次数: 0
Large-Scale Proteomics-Based Risk Score for the Prediction of Incident Cardio-Kidney-Metabolic Disease Risk. 基于大规模蛋白质组学的心肾代谢性疾病风险预测风险评分
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-09-11 DOI: 10.1161/CIRCGEN.124.005125
Adithya K Yadalam, Chang Liu, Qin Hui, Alexander C Razavi, Laurence S Sperling, Arshed A Quyyumi, Yan V Sun
{"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":"https://doi.org/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 male, 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":"2025-09-11","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}
引用次数: 0
Observational and Experimental Evidence on the Interaction Between Fine Particulate Matter and Shared Genetic Variants Across Atherosclerotic Cardiovascular Disease Subtypes. 细颗粒物与动脉粥样硬化性心血管疾病亚型共享遗传变异相互作用的观察和实验证据
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-09-11 DOI: 10.1161/CIRCGEN.124.004986
Jingyi Zhang, Shanshan Ran, Lan Chen, Miao Cai, Fei Tian, Baozhuo Ai, Samantha E Qian, Maya Tabet, Steven W Howard, Yin Yang, Hualiang Lin
{"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":"https://doi.org/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<sub>2.5</sub>) 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<sub>2.5</sub> 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<sub>2.5</sub> 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<sub>2.5</sub> 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<sub>2.5</sub>, potentially influencing atherosclerotic plaque development through inflammation.</p><p><strong>Conclusions: </strong>Our study identified genome-wide loci interacting with PM<sub>2.5</sub> and linked adenosine kinase expression in response to PM<sub>2.5</sub> exposure to the formation of atherosclerotic plaques, highlighting potential pathways that connect PM<sub>2.5</sub> to ASCVD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004986"},"PeriodicalIF":5.5,"publicationDate":"2025-09-11","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}
引用次数: 0
Relationships of Circulating Plasma Metabolites With the QT Interval in a Large Population Cohort. 大人群队列中循环血浆代谢物与QT间期的关系
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-09-11 DOI: 10.1161/CIRCGEN.124.004978
William J Young, Mihir M Sanghvi, Julia Ramírez, Michele Orini, Stefan van Duijvenboden, Helen R Warren, Andrew Tinker, Pier D Lambiase, Patricia B Munroe
{"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":"https://doi.org/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<sup>-</sup><sup>4</sup>) 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":"2025-09-11","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}
引用次数: 0
Age-Dependent Contributions of Rare and Common Genetic Variation in Atrial Fibrillation. 房颤罕见和常见遗传变异的年龄依赖性贡献。
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-09-11 DOI: 10.1161/CIRCGEN.124.004958
Zhanlin Chen, Peter Aziz, Philip Greenland, Rod Passman, Adam Gordon, Gregory Webster
{"title":"Age-Dependent Contributions of Rare and Common Genetic Variation in Atrial Fibrillation.","authors":"Zhanlin Chen, Peter Aziz, Philip Greenland, Rod Passman, Adam Gordon, Gregory Webster","doi":"10.1161/CIRCGEN.124.004958","DOIUrl":"https://doi.org/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":"2025-09-11","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}
引用次数: 0
Genetic Variants Associated With Congenital Heart Disease: A Meta-Analysis of Ethnicity and Subtype-Specific Susceptibility. 与先天性心脏病相关的遗传变异:种族和亚型特异性易感性的荟萃分析
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-08-27 DOI: 10.1161/CIRCGEN.124.005039
Hae Sung Chon, Ji Wan Park
{"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":"https://doi.org/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<sup>-15</sup>), surpassed genome-wide significance. Ethnicity-specific analyses identified 13 significant variants, including <i>MTHFR</i>-rs1801131 in Chinese (<i>P</i>=1.71×10<sup>-10</sup>), <i>STX18-AS1</i>-rs870142 in Europeans (<i>P</i>=7.13×10<sup>-16</sup>), and <i>MTRR</i>-rs1801394 in Middle Eastern populations (<i>P</i>=9.8×10<sup>-8</sup>). 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<sup>-16</sup>) and variants in <i>MTHFR</i>, <i>NRP1</i>, and <i>PTPN11</i> with tetralogy of Fallot (<i>P</i>=3.0×10<sup>-17</sup>-2.33×10<sup>-10</sup>). The rs1801133 variant was linked to double-outlet right ventricle (<i>P</i>=3.0×10<sup>-11</sup>) and patent ductus arteriosus (<i>P</i>=6.5×10<sup>-9</sup>). 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":"2025-08-27","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}
引用次数: 0
Novel Cardiac Troponin-I Missense Variant (c.593C>T) Is Associated With Familial Hypertrophic Cardiomyopathy in Golden Retrievers. 新的心肌肌钙蛋白- 1错义变异(c.593C >t)与金毛猎犬家族性肥厚性心肌病有关。
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-08-22 DOI: 10.1161/CIRCGEN.125.005096
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
{"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":"https://doi.org/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":"2025-08-22","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}
引用次数: 0
Preintervention Intake of Whole Grains Versus Refined Grains, and the Gut Microbiome, Discriminate the Antihypertensive Effect of Prebiotic Fiber. 干预前摄入粗粮与精粮,以及肠道微生物群,区分益生元纤维的降压作用。
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-08-21 DOI: 10.1161/CIRCGEN.124.005019
Matthew Snelson, Dakota Rhys-Jones, Hamdi A Jama, Darren J Creek, Charles R Mackay, Jane Muir, Francine Z Marques
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引用次数: 0
Drug Target Mendelian Randomization: Distinguishing Between Causal Mechanisms and Biomarkers of Those Mechanisms. 药物靶孟德尔随机化:区分因果机制和这些机制的生物标志物。
IF 5.5 2区 医学
Circulation: Genomic and Precision Medicine Pub Date : 2025-08-20 DOI: 10.1161/CIRCGEN.125.005336
Jonathan L Ciofani, Daniel Han, Ravinay Bhindi
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引用次数: 0
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