Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy
{"title":"Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.","authors":"Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy","doi":"10.1161/CIRCGEN.123.004192","DOIUrl":"10.1161/CIRCGEN.123.004192","url":null,"abstract":"<p><strong>Background: </strong>The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.</p><p><strong>Methods: </strong>We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m<sup>2</sup>), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative).</p><p><strong>Results: </strong>In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance.</p><p><strong>Conclusions: </strong>A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004192"},"PeriodicalIF":6.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10940209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139696974","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 Between Genetic Variation in the Targets of Low-Density Lipoprotein-Lowering Drugs and Rheumatoid Arthritis.","authors":"Chenxi Qin, Sara Hägg","doi":"10.1161/CIRCGEN.123.004232","DOIUrl":"10.1161/CIRCGEN.123.004232","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004232"},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138476933","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}
Zachery R Gregorich, Yanghai Zhang, Timothy J Kamp, Henk L Granzier, Wei Guo
{"title":"Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems.","authors":"Zachery R Gregorich, Yanghai Zhang, Timothy J Kamp, Henk L Granzier, Wei Guo","doi":"10.1161/CIRCGEN.123.004355","DOIUrl":"10.1161/CIRCGEN.123.004355","url":null,"abstract":"<p><p>RBM20 (RNA-binding motif protein 20) is a vertebrate- and muscle-specific RNA-binding protein that belongs to the serine-arginine-rich family of splicing factors. The <i>RBM20</i> gene was first identified as a dilated cardiomyopathy-linked gene over a decade ago. Early studies in <i>Rbm20</i> knockout rodents implicated disrupted splicing of RBM20 target genes as a causative mechanism. Clinical studies show that pathogenic variants in <i>RBM20</i> are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality. Subsequent studies employing pathogenic variant knock-in animal models revealed that variants in a specific portion of the arginine-serine-rich domain in RBM20 not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of RBM20 biomolecular condensates in the sarcoplasm. Conversely, mice harboring a disease-associated variant in the RRM (RNA recognition motif) do not show evidence of adverse remodeling or exhibit sudden death despite disrupted splicing of RBM20 target genes. Thus, whether disrupted splicing, biomolecular condensates, or both contribute to dilated cardiomyopathy is under debate. Beyond this, additional questions remain, such as whether there is sexual dimorphism in the presentation of RBM20 cardiomyopathy. What are the clinical features of RBM20 cardiomyopathy and why do some individuals develop more severe disease than others? In this review, we summarize the reported observations and discuss potential mechanisms of RBM20 cardiomyopathy derived from studies employing in vivo animal models and in vitro human-induced pluripotent stem cell-derived cardiomyocytes. Potential therapeutic strategies to treat RBM20 cardiomyopathy are also discussed.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004355"},"PeriodicalIF":6.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10923161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575301","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}
Ayelet Shauer, Smadar Horowitz-Cederboim, Hagar Mor-Shaked, Ronen Durst, Donna R Zwas, Bernard Belhassen
{"title":"Calmodulinopathy Associated Long QT Syndrome, Hypertrophic Cardiomyopathy With Excessive Trabeculation in a 14-Year-Old Girl Presenting With Ventricular Fibrillation.","authors":"Ayelet Shauer, Smadar Horowitz-Cederboim, Hagar Mor-Shaked, Ronen Durst, Donna R Zwas, Bernard Belhassen","doi":"10.1161/CIRCGEN.123.004163","DOIUrl":"10.1161/CIRCGEN.123.004163","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004163"},"PeriodicalIF":7.4,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519059","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}
Aleksandra D Chybowska, Danni A Gadd, Yipeng Cheng, Elena Bernabeu, Archie Campbell, Rosie M Walker, Andrew M McIntosh, Nicola Wrobel, Lee Murphy, Paul Welsh, Naveed Sattar, Jackie F Price, Daniel L McCartney, Kathryn L Evans, Riccardo E Marioni
{"title":"Epigenetic Contributions to Clinical Risk Prediction of Cardiovascular Disease.","authors":"Aleksandra D Chybowska, Danni A Gadd, Yipeng Cheng, Elena Bernabeu, Archie Campbell, Rosie M Walker, Andrew M McIntosh, Nicola Wrobel, Lee Murphy, Paul Welsh, Naveed Sattar, Jackie F Price, Daniel L McCartney, Kathryn L Evans, Riccardo E Marioni","doi":"10.1161/CIRCGEN.123.004265","DOIUrl":"10.1161/CIRCGEN.123.004265","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular disease (CVD) is among the leading causes of death worldwide. The discovery of new omics biomarkers could help to improve risk stratification algorithms and expand our understanding of molecular pathways contributing to the disease. Here, ASSIGN-a cardiovascular risk prediction tool recommended for use in Scotland-was examined in tandem with epigenetic and proteomic features in risk prediction models in ≥12 657 participants from the Generation Scotland cohort.</p><p><strong>Methods: </strong>Previously generated DNA methylation-derived epigenetic scores (EpiScores) for 109 protein levels were considered, in addition to both measured levels and an EpiScore for cTnI (cardiac troponin I). The associations between individual protein EpiScores and the CVD risk were examined using Cox regression (n<sub>cases</sub>≥1274; n<sub>controls</sub>≥11 383) and visualized in a tailored R application. Splitting the cohort into independent training (n=6880) and test (n=3659) subsets, a composite CVD EpiScore was then developed.</p><p><strong>Results: </strong>Sixty-five protein EpiScores were associated with incident CVD independently of ASSIGN and the measured concentration of cTnI (<i>P</i><0.05), over a follow-up of up to 16 years of electronic health record linkage. The most significant EpiScores were for proteins involved in metabolic, immune response, and tissue development/regeneration pathways. A composite CVD EpiScore (based on 45 protein EpiScores) was a significant predictor of CVD risk independent of ASSIGN and the concentration of cTnI (hazard ratio, 1.32; <i>P</i>=3.7×10<sup>-3</sup>; 0.3% increase in C-statistic).</p><p><strong>Conclusions: </strong>EpiScores for circulating protein levels are associated with CVD risk independent of traditional risk factors and may increase our understanding of the etiology of the disease.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004265"},"PeriodicalIF":6.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10876178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139575342","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}
Emanuele Monda, Gaetano Diana, Francesca Graziani, Marta Rubino, Athanasios Bakalakos, Ales Linhart, Dominique P Germain, Maurizio Scarpa, Elena Biagini, Maurizio Pieroni, Perry Mark Elliott, Giuseppe Limongelli
{"title":"Impact of <i>GLA</i> Variant Classification on the Estimated Prevalence of Fabry Disease: A Systematic Review and Meta-Analysis of Screening Studies.","authors":"Emanuele Monda, Gaetano Diana, Francesca Graziani, Marta Rubino, Athanasios Bakalakos, Ales Linhart, Dominique P Germain, Maurizio Scarpa, Elena Biagini, Maurizio Pieroni, Perry Mark Elliott, Giuseppe Limongelli","doi":"10.1161/CIRCGEN.123.004252","DOIUrl":"10.1161/CIRCGEN.123.004252","url":null,"abstract":"<p><strong>Background: </strong>The diagnosis of Fabry disease (FD) has relevant implications related to the management. Thus, a clear assignment of <i>GLA</i> variant pathogenicity is crucial. This systematic review and meta-analysis aimed to investigate the prevalence of FD in high-risk populations and newborns and evaluate the impact of different <i>GLA</i> variant classifications on the estimated prevalence of FD.</p><p><strong>Methods: </strong>We searched the EMBASE and PubMed databases on February 21, 2023. Observational studies evaluating the prevalence of FD and reporting the identified <i>GLA</i> variants were included. <i>GLA</i> variants were re-evaluated for their pathogenicity significance using the American College of Medical Genetics and Genomics criteria and the ClinVar database. The pooled prevalence of FD among different settings was calculated. The study was registered on PROSPERO (CRD42023401663) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.</p><p><strong>Results: </strong>Of the 3941 studies identified, 110 met the inclusion criteria. The pooled prevalence of FD was significantly different according to the clinical setting and criteria used for the pathogenicity assessment. Using the American College of Medical Genetics and Genomics criteria, the pooled prevalence was 1.2% in patients with left ventricular hypertrophy/hypertrophic cardiomyopathy (26 studies; 10 080 patients screened), 0.3% in end-stage renal disease/chronic kidney disease (38 studies; 62 050 patients screened), 0.7% in stroke (25 studies; 15 295 patients screened), 0.7% in cardiac conduction disturbance requiring pacemaker (3 studies; 1033 patients screened), 1.0% in small-fiber neuropathy (3 studies; 904 patients screened), and 0.01% in newborns (15 studies; 11 108 793 newborns screened). The pooled prevalence was different if the <i>GLA</i> variants were assessed using the ClinVar database, and most patients with a discrepancy in the pathogenicity assignment carried 1 of the following variants: p.A143T, p.D313Y, and p.E66Q.</p><p><strong>Conclusions: </strong>This systematic review and meta-analysis describe the prevalence of FD among newborns and high-risk populations, highlighting the need for a periodic reassessment of the <i>GLA</i> variants in the context of recent clinical, biochemical, and histological data.</p><p><strong>Registration: </strong>URL: https://crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42023401663.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004252"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138476871","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}
Jessica Sweeney, Crystal Tichnell, Susan Christian, Catherine Pendelton, Brittney Murray, Debra L Roter, Leila Jamal, Hugh Calkins, Cynthia A James
{"title":"Characterizing Decision-Making Surrounding Exercise in ARVC: Analysis of Decisional Conflict, Decisional Regret, and Shared Decision-Making.","authors":"Jessica Sweeney, Crystal Tichnell, Susan Christian, Catherine Pendelton, Brittney Murray, Debra L Roter, Leila Jamal, Hugh Calkins, Cynthia A James","doi":"10.1161/CIRCGEN.123.004133","DOIUrl":"10.1161/CIRCGEN.123.004133","url":null,"abstract":"<p><strong>Background: </strong>Limiting high-intensity exercise is recommended for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) due to its association with penetrance, arrhythmias, and structural progression. Guidelines recommend shared decision-making (SDM) for exercise level, but there is little evidence regarding its impact. Therefore, we sought to evaluate the extent and implications of SDM for exercise, decisional conflict, and decisional regret in patients with ARVC and at-risk relatives.</p><p><strong>Methods: </strong>Adults diagnosed with ARVC or with positive genetic testing enrolled in the Johns Hopkins ARVC Registry were invited to complete a questionnaire that included exercise history and current exercise, SDM (SDM-Q-9), decisional conflict, and decisional regret.</p><p><strong>Results: </strong>The response rate was 64.8%. Two-thirds of participants (68.0%, n=121) reported clinically significant decisional conflict regarding exercise at diagnosis/genetic testing (DCS [decisional conflict scale]≥25), and half (55.1%, n=98) in the past year. Prevalence of decisional regret was also high with 55.3% (n=99) reporting moderate to severe decisional regret (DRS [decisional regret scale]≥25). The extent of SDM was highly variable ranging from no (0) to perfect (100) SDM (mean, 59.6±25.0). Those diagnosed in adolescence (≤age 21) reported significantly more SDM (<i>P</i>=0.013). Importantly, SDM was associated with less decisional conflict (ß=-0.66, R<sup>2</sup>=0.567, <i>P</i><0.01) and decisional regret (ß=-0.37, R<sup>2</sup>=0.180, <i>P</i><0.001) and no difference in vigorous intensity aerobic exercise in the 6 months after diagnosis/genetic testing or the past year (<i>P</i>=0.56; <i>P</i>=0.34, respectively).</p><p><strong>Conclusions: </strong>SDM is associated with lower decisional conflict and decisional regret; and no difference in postdiagnosis exercise. Our data thus support SDM as the preferred model for exercise discussions for ARVC.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004133"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10729899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138444115","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}
Elizaveta Polyakova, Janine M van Gils, J Lauran Stöger, Philippine Kiès, Anastasia D Egorova, Tamara T Koopmann, Tessa van Dijk, Marco C DeRuiter, Daniela Q C M Barge-Schaapveld, Monique R M Jongbloed
{"title":"New Genetic Variant in the <i>MYH7</i> Gene Associated With Hypoplastic Right Heart Syndrome and Hypertrophic Cardiomyopathy in the Same Family.","authors":"Elizaveta Polyakova, Janine M van Gils, J Lauran Stöger, Philippine Kiès, Anastasia D Egorova, Tamara T Koopmann, Tessa van Dijk, Marco C DeRuiter, Daniela Q C M Barge-Schaapveld, Monique R M Jongbloed","doi":"10.1161/CIRCGEN.123.004184","DOIUrl":"10.1161/CIRCGEN.123.004184","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004184"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41193220","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}
Natalie R Hasbani, Kenneth E Westerman, Soo Heon Kwak, Han Chen, Xihao Li, Daniel Di Corpo, Jennifer Wessel, Joshua C Bis, Chloè Sarnowski, Peitao Wu, Lawrence F Bielak, Xiuqing Guo, Nancy Heard-Costa, Gregory L Kinney, Michael C Mahaney, May E Montasser, Nicholette D Palmer, Laura M Raffield, James G Terry, Lisa R Yanek, Jessica Bon, Donald W Bowden, Jennifer A Brody, Ravindranath Duggirala, David R Jacobs, Rita R Kalyani, Leslie A Lange, Braxton D Mitchell, Jennifer A Smith, Kent D Taylor, April P Carson, Joanne E Curran, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Richard A Gibbs, Namrata Gupta, Sharon L R Kardia, Brian G Kral, Zeineen Momin, Anne B Newman, Wendy S Post, Karine A Viaud-Martinez, Kendra A Young, Lewis C Becker, Alain G Bertoni, John Blangero, John J Carr, Katherine Pratte, Bruce M Psaty, Stephen S Rich, Joseph C Wu, Rajeev Malhotra, Patricia A Peyser, Alanna C Morrison, Ramachandran S Vasan, Xihong Lin, Jerome I Rotter, James B Meigs, Alisa K Manning, Paul S de Vries
{"title":"Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.","authors":"Natalie R Hasbani, Kenneth E Westerman, Soo Heon Kwak, Han Chen, Xihao Li, Daniel Di Corpo, Jennifer Wessel, Joshua C Bis, Chloè Sarnowski, Peitao Wu, Lawrence F Bielak, Xiuqing Guo, Nancy Heard-Costa, Gregory L Kinney, Michael C Mahaney, May E Montasser, Nicholette D Palmer, Laura M Raffield, James G Terry, Lisa R Yanek, Jessica Bon, Donald W Bowden, Jennifer A Brody, Ravindranath Duggirala, David R Jacobs, Rita R Kalyani, Leslie A Lange, Braxton D Mitchell, Jennifer A Smith, Kent D Taylor, April P Carson, Joanne E Curran, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Richard A Gibbs, Namrata Gupta, Sharon L R Kardia, Brian G Kral, Zeineen Momin, Anne B Newman, Wendy S Post, Karine A Viaud-Martinez, Kendra A Young, Lewis C Becker, Alain G Bertoni, John Blangero, John J Carr, Katherine Pratte, Bruce M Psaty, Stephen S Rich, Joseph C Wu, Rajeev Malhotra, Patricia A Peyser, Alanna C Morrison, Ramachandran S Vasan, Xihong Lin, Jerome I Rotter, James B Meigs, Alisa K Manning, Paul S de Vries","doi":"10.1161/CIRCGEN.123.004176","DOIUrl":"10.1161/CIRCGEN.123.004176","url":null,"abstract":"<p><strong>Background: </strong>Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.</p><p><strong>Methods: </strong>We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.</p><p><strong>Results: </strong>Using a Bonferroni-corrected significance threshold of <i>P</i><1.6×10<sup>-4</sup>, we identified 3 genes (<i>ATP1B1</i>, <i>ARVCF</i>, and <i>LIPG</i>) associated with CAC and 2 genes (<i>ABCG8</i> and <i>EIF2B2</i>) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both <i>ATP1B1</i> and <i>ARVCF</i> also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.</p><p><strong>Conclusions: </strong>These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004176"},"PeriodicalIF":6.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10843644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138444119","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}