Circulation: Genomic and Precision Medicine最新文献

{"title":"Family Screening in Patients With Dilated and Arrhythmogenic Cardiomyopathy: The Road Toward Gene-Specific Recommendations.","authors":"Sophie L V M Stroeks, Steven Muller, Nina J Beelen, Max F G H M Venner, Annette F Baas, Vanessa P M van Empel, Ingrid P C Krapels, Mark R Hazebroek, Anneline S J M Te Riele, Job A J Verdonschot","doi":"10.1161/CIRCGEN.124.004778","DOIUrl":"10.1161/CIRCGEN.124.004778","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004778"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001120","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":"Random Survival Forest Machine Learning for the Prediction of Cardiovascular Events Among Patients With a Measured Lipoprotein(a) Level: A Model Development Study.","authors":"Jay B Lusk, Emily C O'Brien, Bradley G Hammill, Fan Li, Brian Mac Grory, Manesh R Patel, Neha J Pagidipati, Nishant P Shah","doi":"10.1161/CIRCGEN.124.004629","DOIUrl":"10.1161/CIRCGEN.124.004629","url":null,"abstract":"<p><strong>Background: </strong>Established risk models may not be applicable to patients at higher cardiovascular risk with a measured Lp(a) (lipoprotein[a]) level, a causal risk factor for atherosclerotic cardiovascular disease.</p><p><strong>Methods: </strong>This was a model development study. The data source was the Nashville Biosciences Lp(a) data set, which includes clinical data from the Vanderbilt University Health System. We included patients with an Lp(a) measured between 1989 and 2022 and who had at least 1 year of electronic health record data before measurement of an Lp(a) level. The end point of interest was time to first myocardial infarction, stroke/TIA, or coronary revascularization. A random survival forest model was derived and compared with a Cox proportional hazards model derived from traditional cardiovascular risk factors (ie, the variables used to estimate the Pooled Cohort Equations for the primary prevention population and the variables used to estimate the Second Manifestations of Arterial Disease and Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention scores for the secondary prevention population). Model discrimination was evaluated using Harrell's C-index.</p><p><strong>Results: </strong>A total of 4369 patients were included in the study (49.5% were female, mean age was 51 [SD 18] years, and mean Lp(a) level was 33.6 [38.6] mg/dL, of whom 23.7% had a prior cardiovascular event). The random survival forest model outperformed the traditional risk factor models in the test set (c-index, 0.82 [random forest model] versus 0.69 [primary prevention model] versus 0.80 [secondary prevention model]). These results were similar when restricted to a primary prevention population and under various strategies to handle competing risk. A Cox proportional hazard model based on the top 25 variables from the random forest model had a c-index of 0.80.</p><p><strong>Conclusions: </strong>A random survival forest model outperformed a model using traditional risk factors for predicting cardiovascular events in patients with a measured Lp(a) level.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004629"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022422","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":"Lipoprotein(a) Atherosclerotic Cardiovascular Disease Risk Score Development and Prediction in Primary Prevention From Real-World Data.","authors":"Wenjun Fan, Chuyue Wu, Nathan D Wong","doi":"10.1161/CIRCGEN.124.004631","DOIUrl":"10.1161/CIRCGEN.124.004631","url":null,"abstract":"<p><strong>Background: </strong>Lipoprotein(a) [Lp(a)] is a predictor of atherosclerotic cardiovascular disease (ASCVD); however, there are few algorithms incorporating Lp(a), especially from real-world settings. We developed an electronic health record (EHR)-based risk prediction algorithm including Lp(a).</p><p><strong>Methods: </strong>Utilizing a large EHR database, we categorized Lp(a) cut points at 25, 50, and 75 mg/dL and constructed 10-year ASCVD risk prediction models incorporating Lp(a), with external validation in a pooled cohort of 4 US prospective studies. Net reclassification improvement was determined among borderline-intermediate risk patients.</p><p><strong>Results: </strong>We included 5902 patients aged ≥18 years (mean age 48.7±16.7 years, 51.2% women, and 7.7% Black). Our EHR model included Lp(a), age, sex, Black race/ethnicity, systolic blood pressure, total and high-density lipoprotein cholesterol, diabetes, smoking, and hypertension medication. Over a mean follow-up of 6.8 years, ASCVD event rates (per 1000 person-years) ranged from 8.7 to 16.7 across Lp(a) groups. A 25 mg/dL increment in Lp(a) was associated with an adjusted hazard ratio of 1.23 (95% CI, 1.10-1.37) for composite ASCVD. Those with Lp(a) ≥75 mg/dL had an 88% higher risk of ASCVD (hazard ratio, 1.88 [95% CI, 1.30-2.70]) and more than double the risk of incident stroke (hazard ratio, 2.55 [95% CI, 1.54-4.23]). C-statistics for our EHR and EHR+Lp(a) models in our EHR training data set were 0.7475 and 0.7556, respectively, with external validation in our pooled cohort (n=21 864) of 0.7350 and 0.7368, respectively. Among those at borderline/intermediate risk, the net reclassification improvement was 21.3%.</p><p><strong>Conclusions: </strong>We show the feasibility of developing an improved ASCVD risk prediction model incorporating Lp(a) based on a real-world adult clinic population. The inclusion of Lp(a) in ASCVD prediction models can reclassify risk in patients who may benefit from more intensified ASCVD prevention efforts.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004631"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028076","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":"Atrial Fibrillation Related Titin Truncation Is Associated With Atrial Myopathy in Patient-Derived Induced Pluripotent Stem Cell Disease Models.","authors":"Kate Huang, Mishal Ashraf, Leili Rohani, Yinhan Luo, Ardin Sacayanan, Haojun Huang, Anne Haegert, Stanislav Volik, Funda Sar, Stéphane LeBihan, Janet Liew, Peter H Backx, Jason D Roberts, Glen F Tibbits, Jared M Churko, Shubhayan Sanatani, Colin Collins, Liam R Brunham, Zachary Laksman","doi":"10.1161/CIRCGEN.123.004412","DOIUrl":"10.1161/CIRCGEN.123.004412","url":null,"abstract":"<p><strong>Background: </strong>Protein-truncating mutations in the titin gene are associated with increased risk of atrial fibrillation. However, little is known about the underlying pathophysiology.</p><p><strong>Methods: </strong>We identified a heterozygous titin truncating variant (TTNtv) in a patient with unexplained early onset atrial fibrillation and normal ventricular function. We generated patient-specific atrial- and ventricular-like induced pluripotent stem cell-derived cardiomyocytes and engineered heart tissue to evaluate the impact of the TTNtv on electrophysiology, sarcomere structure, contractility, and gene expression.</p><p><strong>Results: </strong>We demonstrate that the TTNtv increases susceptibility to pacing-induced arrhythmia, promotes sarcomere disorganization, and reduces contractile force in atrial induced pluripotent stem cell-derived cardiomyocytes compared with their CRISPR/Cas9-corrected isogenic controls. In ventricular induced pluripotent stem cell-derived cardiomyocytes, this variant was associated with abnormal electrophysiology and sarcomere organization without a reduction in contractile force compared with their isogenic controls. RNA-sequencing revealed an upregulation of cell adhesion and extracellular matrix genes in the presence of the TTNtv for both atrial and ventricular engineered heart tissues.</p><p><strong>Conclusions: </strong>In a patient with unexplained atrial fibrillation, induced pluripotent stem cell-derived cardiomyocytes with a TTNtv showed structural and electrophysiological abnormalities in both atrial and ventricular models, while only atrial engineered heart tissues demonstrated reduced contractility. The observed chamber-specific effect suggests that structural disorganization and reduced contractile function may be associated with atrial myopathy in the presence of truncated titin.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004412"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028074","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":"Mono and Biallelic Variants in <i>TRIM63</i> Are Frequently Associated With a Unique Form of Hypertrophic Cardiomyopathy.","authors":"Noa Ruhrman Shahar, Dina Marek-Yagel, Rotem Greenberg, Ofer Isakov, Michal Naftali, Elena Friedman, Lily Bazak, Daniel Monakier, Alvit Veber, Nechama Shalva, Amitai Segev, Moti Haim, Lena Sagi-Dain, Lilach Benyamini, Adel Shalata, Sagi Josefsberg Ben Yehoshua, Lina Basel Salmon, Sara Hoss, Shay Ben-Shachar","doi":"10.1161/CIRCGEN.124.004864","DOIUrl":"10.1161/CIRCGEN.124.004864","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004864"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045646","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":"Lateral Atrial Expression Patterns Provide Insights into Local Transcription Disequilibrium Contributing to Disease Susceptibility.","authors":"Aaron Isaacs, Stef Zeemering, Joris Winters, Montserrat Batlle, Elham Bidar, Bas Boukens, Barbara Casadei, Winnie Chua, Harry J G M Crijns, Larissa Fabritz, Eduard Guasch, Stephane N Hatem, Ben Hermans, Stefan Kääb, Michal Kawczynski, Bart Maesen, Jos Maessen, Lluis Mont, Moritz F Sinner, Reza Wakili, Sander Verheule, Paulus Kirchhof, Ulrich Schotten, Monika Stoll","doi":"10.1161/CIRCGEN.124.004594","DOIUrl":"10.1161/CIRCGEN.124.004594","url":null,"abstract":"<p><strong>Background: </strong>Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease etiology. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrium (LA) and right atrium (RA) may provide insight into diseases such as atrial fibrillation.</p><p><strong>Methods: </strong>Lateral differences in atrial transcription were evaluated in CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly) using a 2-stage discovery and replication design. The design took advantage of the availability of 32 paired samples, for which both LA and RA tissue were obtained, as a discovery cohort, and 98 LA and 69 RA unpaired samples utilized as a replication cohort.</p><p><strong>Results: </strong>A total of 714 transcripts were identified and replicated as differentially expressed (DE) between LA and RA, as well as 98 exons in 55 genes. Approximately 50% of DE transcripts were colocated with another frequently correlated DE transcript (<i>P</i>_FDR ≤0.05 for 579 regions). These \"transcription disequilibrium\" blocks contained examples including side-specific differential exon usage, such as the <i>PITX2</i> locus, where <i>ENPEP</i> showed evidence of differential exon usage. Analysis of this region in conjunction with <i>BMP10</i> identified rs9790621 as associated with <i>ENPEP</i> transcription in LA, while rs7687878 was associated with <i>BMP10</i> expression in RA. In RA, <i>BMP10</i> and <i>ENPEP</i> were strongly correlated in noncarriers, which was attenuated in risk-allele carriers, where <i>BMP10</i> and <i>PITX2</i> expression were strongly correlated.</p><p><strong>Conclusions: </strong>These results significantly expand knowledge of the intricate, tissue-specific transcriptional landscape in human atria, including DE transcripts and side-specific isoform expression. Furthermore, they suggest the existence of blocks of transcription disequilibrium influenced by genetics.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004594"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022414","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":"Sex-Specific Clinical and Genetic Factors Associated With Adverse Outcomes in Hypertrophic Cardiomyopathy.","authors":"Alexandra Butters, Clare Arnott, Joanna Sweeting, Brian Claggett, Anna Se Cuomo, Dominic Abrams, Euan A Ashley, Sharlene M Day, Adam S Helms, Rachel Lampert, Kim Y Lin, Michelle Michels, Erin M Miller, Iacopo Olivotto, Anjali Owens, Victoria N Parikh, Alexandre C Pereira, Joseph W Rossano, Thomas D Ryan, Sara Saberi, John C Stendahl, James S Ware, John Atherton, Christopher Semsarian, Neal K Lakdawala, Carolyn Y Ho, Jodie Ingles","doi":"10.1161/CIRCGEN.124.004641","DOIUrl":"10.1161/CIRCGEN.124.004641","url":null,"abstract":"<p><strong>Background: </strong>Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry.</p><p><strong>Methods: </strong>Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for females and males to find the sex-specific hazard ratio (HR).</p><p><strong>Results: </strong>After a mean follow-up of 6.4 years, females had a higher risk of heart failure (HR, 1.51 [95% CI, 1.21-1.88]; <i>P</i>=0.0003) but a lower risk of atrial fibrillation (HR, 0.74 [95% CI, 0.59-0.93]; <i>P</i><0.0001) and ventricular arrhythmia (HR, 0.60 [95% CI, 0.38-0.94]; <i>P</i>=0.027) than males. No sex difference was observed for death (<i>P</i>=0.84). Sarcomere-positive males had higher heart failure (HR, 1.34 [95% CI, 1.06-1.69]) and death risks (HR, 1.48 [95% CI, 1.08-2.04]) not seen in females (HR, 0.85 [95% CI, 0.66-1.08] versus HR, 0.86 [95% CI, 0.71-1.21]). <i>MYBPC3</i> variants lowered heart failure risk in females (HR, 0.56 [95% CI, 0.41-0.77]) but not in males (HR, 1.29 [95% CI, 0.99-1.67]). A sex difference appeared in moderate (4% to <6%) versus low risk (<4%) European Society of Cardiology hypertrophic cardiomyopathy risk score, with females at moderate risk more prone to ventricular arrhythmia (HR, 3.57 [95% CI, 1.70-7.49]), unobserved in males (HR, 1.13 [95% CI, 0.63-2.03]).</p><p><strong>Conclusions: </strong>We found that clinical and genetic factors contributing to adverse outcomes in hypertrophic cardiomyopathy affect females and males differently. Thus, research to inform sex-specific management of hypertrophic cardiomyopathy could improve outcomes for both sexes.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004641"},"PeriodicalIF":6.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028078","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":"Yield of Genetic Testing for Long-QT Syndrome in Elderly Patients With Torsades de Pointes.","authors":"Daiki Tomidokoro, Toshihiro Nakamura, Satoshi Oka, Yuichiro Miyazaki, Akionori Wakamiya, Nobuhiko Ueda, Kenzaburo Nakajima, Tsukasa Kamakura, Mitsuru Wada, Kohei Ishibashi, Yuko Inoue, Koji Miyamoto, Satoshi Nagase, Shuichi Kitada, Yu Sakaue, Hirokazu Shiraishi, Tomoyuki Kabutoya, Kaoru Takami, Miwa Miyoshi, Naohiko Takahashi, Takeshi Soeki, Yukio Hiroi, Yoshihiro Asano, Seiko Ohno, Kengo Kusano, Takeshi Aiba","doi":"10.1161/CIRCGEN.124.004671","DOIUrl":"10.1161/CIRCGEN.124.004671","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004671"},"PeriodicalIF":6.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521173","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":"Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating <i>MYBPC3</i> Founder Variant Carriers.","authors":"Fahima Hassanzada, Mark Jansen, Freyja H M van Lint, Laurens P Bosman, Amand F Schmidt, Dennis Dooijes, Danny van de Sande, Bristi Miah, Saskia N van der Crabben, Arthur A M Wilde, Ronald H Lekanne Deprez, Rudolf A de Boer, Imke Christiaans, Jan D H Jongbloed, Harald T Jorstad, Folkert W Asselbergs, J Peter van Tintelen, Annette F Baas, Anneline S J M Te Riele","doi":"10.1161/CIRCGEN.124.004561","DOIUrl":"10.1161/CIRCGEN.124.004561","url":null,"abstract":"<p><strong>Background: </strong><i>MYBPC3</i> founder variants cause hypertrophic cardiomyopathy leading to heart failure and malignant ventricular arrhythmias. Exercise is typically regarded as a risk factor for disease expression although evidence is conflicting. Stratifying by type of exercise may discriminate low- from high-risk activities in these patients. Here, we evaluate the effects of exercise, stratified by high-static and high-dynamic components, on the risk of major cardiomyopathy-related events (MCEs) and cardiomyopathy penetrance among <i>MYBPC3</i> founder variant carriers.</p><p><strong>Methods: </strong>We interviewed 188 carriers (57.4% male; aged 43.0±15.0 years) on exercise participation since the age of 10 years. The exercise was quantified as the metabolic equivalent of task-h/wk before the presentation. MCE was defined as a composite of malignant ventricular arrhythmia (sustained ventricular tachycardia/fibrillation), heart failure (heart failure hospitalizations or transplantation), and septal reduction therapy. Static and dynamic exercises were defined per the Bethesda classification. Associations of exercise with MCE and cardiomyopathy penetrance were adjusted for sex and assessed using Cox regression.</p><p><strong>Results: </strong>Overall, 43 (22.9%) subjects experienced MCE and 139 (73.9%) were diagnosed with cardiomyopathy. No association was found between overall physical activity and high-static activity with MCE (<i>P</i>=0.587 overall; <i>P</i>=0.322 high static) or cardiomyopathy penetrance (<i>P</i>=0.317 overall; <i>P</i>=0.623 high static). In contrast, high-dynamic activity was associated with malignant ventricular arrhythmia (dichotomized at the 75th percentile: adjusted hazard ratio, 3.26 [95% CI, 1.26-8.44]; <i>P</i>=0.015).</p><p><strong>Conclusions: </strong>Overall exercise participation does not generally increase the risk of adverse events among <i>MYBPC3</i> founder variant carriers. Nonetheless, an increased risk of malignant ventricular arrhythmia was observed among those engaged in the highest quartile of high-dynamic sports, suggesting that high-level high-intensity exercise activities should be entertained with caution.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":"17 6","pages":"e004561"},"PeriodicalIF":6.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846138","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 Noncoding RNA TRIBAL Links the 8q24.13 Locus to Hepatic Lipid Metabolism and Coronary Artery Disease.","authors":"Sébastien Soubeyrand, Paulina Lau, Majid Nikpay, Lijiang Ma, Johan L M Bjorkegren, Ruth McPherson","doi":"10.1161/CIRCGEN.124.004674","DOIUrl":"10.1161/CIRCGEN.124.004674","url":null,"abstract":"<p><strong>Background: </strong>Genome-wide association studies identified a 20-Kb region of chromosome 8 (8q24.13) associated with plasma lipids, hepatic steatosis, and risk for coronary artery disease. The region is proximal to <i>TRIB1</i>, and given its well-established role in lipid regulation in animal models, TRIB1 has been proposed to mediate the contribution of the 8q24.13 locus to these traits. This region overlaps a gene encoding the primate-specific long noncoding RNA transcript <i>TRIBAL</i>/<i>TRIB1AL</i> (<i>TRIB1</i>-associated locus), but the contribution of TRIBAL to coronary artery disease risk remains untested.</p><p><strong>Methods: </strong>Using recently available expression quantitative trait loci data and hepatocyte models, we further investigated this locus by Mendelian randomization analysis. Following antisense oligonucleotide targeting of TRIBAL, transcription array, quantitative reverse transcription polymerase chain reaction, and enrichment analyses were performed and effects on apoB and triglyceride secretion were determined.</p><p><strong>Results: </strong>Mendelian randomization analysis supports a causal relationship between genetically determined hepatic <i>TRIBAL</i> expression and markers of hepatic steatosis and coronary artery disease risk. By contrast, expression data sets did not support expression quantitative trait loci relationships between coronary artery disease-associated variants and <i>TRIB1</i>. <i>TRIBAL</i> suppression reduced the expression of key regulators of triglyceride metabolism and bile acid synthesis. Enrichment analyses identified patterns consistent with impaired metabolic functions, including reduced triglyceride and cholesterol handling ability. Furthermore, <i>TRIBAL</i> suppression was associated with reduced hepatocyte secretion of triglycerides.</p><p><strong>Conclusions: </strong>This work identifies <i>TRIBAL</i> as a gene bridging the genotype-phenotype relationship at the 8q24.13 locus with effects on genes regulating hepatocyte lipid metabolism and triglyceride secretion.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004674"},"PeriodicalIF":6.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766786","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}