Circulation: Genomic and Precision Medicine最新文献

{"title":"FGF12 Alleviates Cardiac Hypertrophy by Inhibiting Phosphorylation of CaM/CaMKII/CREB1 Axis.","authors":"Taojun Zhang, Kunlun Yin, Tianjiao Li, Shuiyun Wang, Zhou Zhou","doi":"10.1161/CIRCGEN.125.005362","DOIUrl":"10.1161/CIRCGEN.125.005362","url":null,"abstract":"<p><strong>Background: </strong>Hypertrophic cardiomyopathy (HCM) arises from genetic mutations in sarcomere proteins, resulting in major structural abnormalities and limited treatment options. Patients with HCM had reduced expression of the FGF12 (fibroblast growth factor 12), but its precise functional role remains unclear.</p><p><strong>Methods: </strong>To explore FGF12's function and interactions, we utilized clustered regularly interspaced short palindromic repeats-Cas9 technology in cardiomyocytes derived from human induced pluripotent stem cells-induced cardiomyocytes, as well as in other cell lines and mouse models (MYH7^R403Q/+, MYBPC3^{c790GtoA/c790GtoA}, and transverse aortic constriction models). We transfected HCM or mice model with FGF12-coding sequence and FGF12-ΔNLS plasmids or adeno-associated virus 9 vectors to reduce myocardial hypertrophy. As hypertrophy progressed, we used cleavage under targets and tagmentation) sequencing and AlphaFold3 on myocardial tissues from patients and induced pluripotent stem cells-induced cardiomyocytes. To predict mitochondrial function in cardiomyocytes, we measured mitochondrial Ca²⁺ concentrations and reactive oxygen species content.</p><p><strong>Results: </strong>First, we observed a decrease in FGF12 expression and a difference in its subcellular localization in patients with HCM compared with healthy volunteers. In hypertrophic mouse models, injecting adeno-associated virus 9 reduced myocardial hypertrophy. FGF12 binds to calmodulin and inhibits its phosphorylation. This interaction also suppresses the expression and phosphorylation of downstream proteins, including CaMKII, ERK1/2, CREB1, and MCU. The nuclear-localization FGF12 binds to the promoter region of CREB1. FGF12 inhibits the expression of the CREB1-MCU axis expression, leading to reductions in both mitochondrial Ca²⁺ concentration and mitochondrial reactive oxygen species.</p><p><strong>Conclusions: </strong>This study reveals a pathological mechanism associated with HCM linked to FGF12. FGF12, located outside the nucleus, suppresses the expression of metabolism-related genes by reducing the phosphorylation levels within the calmodulin-ERK1/2-CREB1-MCU axis. In contrast, the nuclear localization of FGF12 facilitates its binding to the promoter regions of CREB1, inhibiting CREB1 expression. This dual action maintains cardiomyocyte function and mitochondrial homeostasis. Our findings position FGF12 as a promising therapeutic target for HCM.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005362"},"PeriodicalIF":6.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670776","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":"Newfoundland Mutation <i>TMEM43</i>-p.S358L Causes Impaired Cardiac Energy Metabolism and Mitochondrial Function Through Altered Protein Interaction.","authors":"Sandra Ratnavadivel, Kai Jürgens, Nora Klinke, Anna Gärtner, Joline Groß, Karin Klingel, Anders Malmendal, Stefan Walter, Hanne Boen, Emeline Van Craenenbroeck, René Schramm, Anna Kostareva, Jan Gummert, Astrid Kassner, Heiko Meyer, Achim Paululat, Hendrik Milting","doi":"10.1161/CIRCGEN.125.005171","DOIUrl":"10.1161/CIRCGEN.125.005171","url":null,"abstract":"<p><strong>Background: </strong>TMEM43 (transmembrane protein 43) is a ubiquitously expressed 4-transmembrane-protein localized in the endoplasmic reticulum and nuclear lamina. The missense mutation <i>TMEM43</i>-p.S358L causes fully penetrant ARVC5 (arrhythmogenic right ventricular cardiomyopathy type 5) especially in males. The TMEM43 function of the protein and the pathomechanisms of TMEM43-p.S358L remain poorly understood. We analyzed carrier-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), human myocardial tissue from TMEM43-wild-type, and TMEM43-p.S358L and identified differentially interacting proteins. Here we provide evidence for a novel pathomechanism contributing to the onset of ARVC5.</p><p><strong>Methods: </strong>Microsomes of human wild-type myocardium were separated by sucrose-gradient ultracentrifugation and characterized by mass-spectrometry to identify potential interacting proteins. Proteome and metabolome analyses of a <i>TMEM43</i>-p.S358L explanted human myocardium were performed. hiPSC-derived cardiomyocytes of <i>TMEM43</i>-p.S358L carrier and a corresponding isogenic control were generated. A 3'-end HA-Tag was introduced in <i>TMEM43</i> for pull-down experiments under optimized conditions. Lipidomics, proteomics, contractility, and ATP-content were measured in hiPSC-CMs.</p><p><strong>Results: </strong>Pull-down analyses of TMEM43-WT and mutant showed altered interacting proteins involved in metabolic pathways. Lipidomics revealed the accumulation of lipids and decreased lipid metabolism capacity in mutant hiPSC-CMs. The ATP to ADP ratio was lower in mutant hiPSC-CMs and could be associated with diminished contraction frequency. The human <i>TMEM43</i>-p.S358L myocardial proteome revealed altered protein-expression of metabolic pathways comparable to mutant hiPSC-CMs. Metabolic remodeling was also found in the mutant human myocardium. Ultracentrifugation fraction with the highest protein amount of TMEM43 and pull-down experiments of hiPSC-CMs revealed differentially interacting proteins of TMEM43-p.S358L from endoplasmic reticulum and mitochondrial membranes.</p><p><strong>Conclusions: </strong>We suggest differential interaction of mutant TMEM43 with proteins of mitochondria and endoplasmic reticulum influences endoplasmic reticulum-mitochondrial contact sites. <i>TMEM43</i>-p.S358L primarily contributes to changes in mitochondrial function affecting lipid homeostasis and energy supply.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005171"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590336","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":"Evaluation of Women With Peripartum or Dilated Cardiomyopathy and Their First-Degree Relatives: The DCM Precision Medicine Study.","authors":"Evan P Kransdorf, Rashmi Jain, Jonathan O Mead, Garrie Haas, Mark Hofmeyer, Gregory A Ewald, Jamie Diamond, Anjali Owens, Brian Lowes, Douglas Stoller, W H Wilson Tang, Mark H Drazner, Cindy M Martin, Palak Shah, Jose Tallaj, Stuart Katz, Javier Jimenez, Supriya Shore, Frank Smart, Jessica Wang, Stephen S Gottlieb, Daniel P Judge, Gordon S Huggins, Jason Cowan, Patricia Parker, Jinwen Cao, Natalie S Hurst, Elizabeth Jordan, Hanyu Ni, Daniel D Kinnamon, Ray E Hershberger","doi":"10.1161/CIRCGEN.125.005541","DOIUrl":"10.1161/CIRCGEN.125.005541","url":null,"abstract":"<p><strong>Background: </strong>Rare variant genetics have been associated with peripartum cardiomyopathy (PPCM), but the role of genetics remains unsettled. The study sought to compare dilated cardiomyopathy (DCM) genetic risk in first-degree relatives (FDRs) of female patients (probands) with DCM or PPCM to gain causal inference, and to assess DCM-relevant rare variant prevalence in DCM/PPCM probands and population controls.</p><p><strong>Methods: </strong>Clinical and genetic data were analyzed from the DCM Precision Medicine Study. Risk of DCM or partial DCM, where partial DCM was defined as left ventricular enlargement or a left ventricular ejection fraction of <50%, was estimated in 665 FDRs from 452 female probands, all of whom had been pregnant; 67 had PPCM and 385 had DCM; prevalence of pathogenic, likely pathogenic, or uncertain significance variants was estimated among probands.</p><p><strong>Results: </strong>The risk of DCM/partial DCM for FDRs of PPCM probands was similar to that for FDRs of DCM probands (hazard ratio, 0.77 [95% CI, 0.47-1.28]). Estimated DCM prevalence among the lowest-risk FDRs of non-Hispanic European ancestry probands with PPCM (7.0% [95% CI, 0%-14.1%] females, 9.0% [95% CI, 1.6%-16.3%] males) exceeded population estimates from a UK Biobank study (0.30% females, 0.63% males). Estimated prevalences of a pathogenic, likely pathogenic, or uncertain significance variant among African ancestry and European ancestry probands with PPCM were 55.4% (95% CI, 33.1%-77.7%) and 66.0% (95% CI, 38.6%-93.3%), respectively. The estimated prevalence of pathogenic/likely pathogenic variants among European ancestry PPCM probands (26.6% [95% CI, 12.6%-40.6%]) exceeded a population estimate from a UK Biobank study (0.6%).</p><p><strong>Conclusions: </strong>The risk of DCM/partial DCM among FDRs was similar regardless of whether their probands had PPCM or DCM. Also, DCM-relevant rare variant findings for females with PPCM or DCM were similar and greater than in population controls, suggesting a similar causal basis for PPCM and DCM. These findings underscore the need for genetic evaluations in all patients with PPCM.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005541"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13020676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510029","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":"Integrative Proteomic and Lipidomic Analysis of Patients With Acute Myocardial Infarction Treated With PCSK9 Antibodies and Statins.","authors":"Lukas E Schmidt, Sean A Burnap, Bhawana Singh, Kaloyan Takov, Sylvain Losdat, Lore Schrutka, Lukas Galli, Konstantinos Theofilatos, Georg W Otto, Christian Hengstenberg, Ioanna Tzoulaki, Irene M Lang, Konstantinos C Koskinas, Walter S Speidl, Lorenz Räber, Manuel Mayr","doi":"10.1161/CIRCGEN.125.005345","DOIUrl":"10.1161/CIRCGEN.125.005345","url":null,"abstract":"<p><strong>Background: </strong>PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition is a potent cholesterol-lowering strategy. This study examined the effects of PCSK9 monoclonal antibodies (mAbs) and high-intensity statins beyond low-density lipoprotein cholesterol reduction, which are not fully defined, particularly in patients with acute myocardial infarction (MI).</p><p><strong>Methods: </strong>Proteomic and lipidomic analyses were conducted on plasma from 265 patients with acute MI from the PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) randomized, placebo-controlled PCSK9 mAb trial and 34 patients without MI with hyperlipidemia from the Vienna Lipid Clinic registry, also receiving PCSK9 mAbs.</p><p><strong>Results: </strong>Discovery proteomics revealed changes in apolipoproteins and increased PCOLCE (procollagen C-endopeptidase enhancer 1) levels in both the PCSK9 mAb and placebo groups after MI. UK Biobank data confirmed PCOLCE and PCSK9 upregulation as associated with statin use. Hepatoma cell experiments demonstrated a dose-dependent PCOLCE induction on statin treatment. Compared with placebo (statins only), PCSK9 mAb therapy resulted in greater reductions in APOB (apolipoprotein B), APOE (apolipoprotein E), APOC2 (apolipoprotein C2), and APOC3 (apolipoprotein C3), as shown by targeted proteomics. Mediation analysis indicated that these changes were largely explained by low-density lipoprotein cholesterol lowering. Lipidomics identified more pronounced reductions in cholesteryl esters, ceramides, sphingomyelins, phosphatidylcholines, triglycerides, and diglycerides in PCSK9 mAb-treated patients with MI. Results were largely consistent in patients without MI. However, levels of LPA (apolipoprotein[a]), the characteristic protein component of lipoprotein(a), remained unchanged in PCSK9 mAb-treated patients with MI, since a rise of LPA was observed in the placebo group post-MI.</p><p><strong>Conclusions: </strong>Most apolipoprotein changes after PCSK9 mAb therapy following MI were mediated by low-density lipoprotein cholesterol lowering. Statin use is associated with increased circulating PCOLCE, with hepatoma cell experiments supporting a predominant hepatic origin. Combining PCSK9 mAbs with high-intensity statins mitigates post-MI increases in lipoprotein(a).</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT03067844.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005345"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149312","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":"Structural Evaluation of <i>RYR2</i>-CPVT Missense Variants and Continuous Bayesian Estimates of Their Penetrance.","authors":"Kundivy Dauda, Kohei Yamauchi, Matthew Ku, Devyn W Mitchell, Alex Shen, Loren Vanags, Jeffrey Schmeckpeper, Prince J Kannankeril, Bjorn C Knollmann, Matthew J O'Neill, Brett M Kroncke","doi":"10.1161/CIRCGEN.125.005457","DOIUrl":"10.1161/CIRCGEN.125.005457","url":null,"abstract":"<p><strong>Background: </strong>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is strongly associated with rare missense variants in <i>RYR2</i>, the gene encoding the intracellular calcium release channel RyR2.</p><p><strong>Methods: </strong>We curated 179 articles reviewed by 3 individuals to extrapolate <i>RYR2</i>-CPVT missense variant genotype-phenotype relationships. Purportedly neutral control variants were ascertained from <i>RYR2</i> missense variants observed in gnomAD and ClinVar. We performed an <i>RYR2</i>-CPVT Bayesian penetrance analysis by conditioning a CPVT penetrance prior (hereafter called Bayesian CPVT-prior) on variant-specific features (in silico and structural) calibrated by heterozygote phenotypes. We evaluated various features, including the Bayesian CPVT-prior, ClinVar, REVEL, and AlphaMissense against our observed CPVT penetrance, using Spearman rank-order correlations and Brier Scores. Penetrance estimates were superimposed on a cryo-EM structure of RyR2 to investigate hot-spot heterogeneity.</p><p><strong>Results: </strong>From the literature, we identified 1014 affected missense <i>RYR2</i> heterozygotes (468 unique variants), and further supplemented by purpuroted unaffected heterozygotes in GnomAD to a total of 622 575 heterozygotes (5181 unique variants). Among the predictors, the Bayesian CPVT-prior score had the highest Spearman rank-order and lowest Brier scores, respectively (0.19; 0.0090), compared with ClinVar (0.083; 0.019), REVEL (0.16; 0.018), or AlphaMissense (0.18; 0.018). Penetrance estimates for all <i>RYR2</i> missense variants are prospectively hosted at the Variant Browser website.</p><p><strong>Conclusions: </strong>Traditional categorical variant annotations limit accurate disease risk assessment, especially in populations unascertained for disease. A probabilistic, population-calibrated penetrance framework enables more meaningful prospective variant interpretation. Our Bayesian CPVT-prior outperforms current tools in evaluating RYR2 variant penetrance. We provide prospective Bayesian CPVT penetrance values for 29 242 RYR2 missense variants at our online variant browser.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005457"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147519959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Twenty-Five-Year Follow-Up of the MDDC1 Family: A <i>LMNA</i> Gene Variant Associated With Dilated Cardiomyopathy With Variable Skeletal Muscle Involvement.","authors":"Teresa Maria Capovilla, Manuela Iseppi, Salvatore Distaso, Marta Gigli, Matteo Dal Ferro, Michele Moretti, Annamaria Iorio, Antonella Mancinelli, Marco Merlo, Luisa Mestroni, Alessia Paldino, Gianfranco Sinagra","doi":"10.1161/CIRCGEN.125.005528","DOIUrl":"10.1161/CIRCGEN.125.005528","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005528"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenome-Wide Mendelian Randomization Identifying Circulating Proteins for Cardiovascular Traits in Populations of African Ancestry.","authors":"Susannah Selber-Hnatiw, Katerina Trajanoska, Justin Pelletier, Chen-Yang Su, Peyton McClelland, Daniel Taliun, Satoshi Yoshiji, Vincent Mooser, Claude Bhérer, Sirui Zhou","doi":"10.1161/CIRCGEN.125.005159","DOIUrl":"10.1161/CIRCGEN.125.005159","url":null,"abstract":"<p><strong>Background: </strong>Circulating proteins represent robust drug targets with therapeutic potential. Many discoveries have focused on European-ancestry populations, disregarding minuscule yet substantial proteomic differences that may contribute to disease and alter drug generalizability in other ancestry groups.</p><p><strong>Methods: </strong>Using 2-sample Mendelian randomization and colocalization, we analyzed the effects of 1562 circulating proteins on 145 cardiometabolic-centric outcomes to identify robust protein-phenotype associations in African-ancestry populations and reveal African-ancestry associations with heterogeneous effects. We further replicated these findings using the proteomic data available from the UK Biobank Pharma Proteomics Project and tested the effect of protein quantity in association with select phenotypes. Population branch statistics were also constructed to examine whether protein-genetic instruments under natural selection could lead to significant protein-outcome associations specific to the African ancestry.</p><p><strong>Results: </strong>We identified 115 robust protein target-outcome associations in African-ancestry populations. Among these, 51 demonstrated heterogeneous effects between African- and European-ancestry populations. We further replicated 4 cross-platform African-ancestry associations in the UK Biobank Pharma Proteomics Project and also revealed 4 significant, direct associations between protein levels and phenotypes. Ultimately, based on our prioritization criteria, we found that CD36 (glycoprotein IIIb), APOC1 (apolipoprotein C1), GSTA1 (glutathione S-transferase alpha 1), and FOLH1 (folate hydrolase 1) were shown to influence lipids and heart diseases, and were uniquely represented in African-ancestry populations. In addition, using population branch statistics, we showed that 47.5% of the 115 significant protein-outcome associations were possibly driven by <i>cis</i>-acting protein quantitative trait loci under natural selection.</p><p><strong>Conclusions: </strong>Multiple lines of evidence were used to interrogate proteomic determinants of cardiometabolic diseases and traits in African-ancestry populations. We highlighted actionable circulating protein targets that could represent potential drug targets for cardiovascular diseases specific to populations with African ancestry.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005159"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Friend of GATA2 Variant Ser657Gly Is Associated With Coronary Microvascular Disease.","authors":"Marie A Guerraty, Shefali S Verma, Yi-An Ko, Michael A McQuillan, Donna M Conlon, John W Tobias, Michael G Levin, William Haury, Fangyuan Zheng, Tess Cherlin, Chao Zhang, Renae Judy, Sarah A Tishkoff, Scott M Damrauer, Zoltan Arany, Daniel J Rader","doi":"10.1161/CIRCGEN.125.005342","DOIUrl":"10.1161/CIRCGEN.125.005342","url":null,"abstract":"<p><strong>Background: </strong>The coronary microvasculature is crucial for proper cardiac function, and coronary microvascular disease (CMVD) has emerged as an underdiagnosed and undertreated cause of ischemic heart disease. FOG2 (friend of GATA 2) is a transcriptional co-regulator crucial for coronary development and the maintenance of the coronary microvasculature in adult mice. Little is known about the role of FOG2 in humans or its role in CMVD. Here, we report a genotype-first approach to determine the role of FOG2 in human CMVD.</p><p><strong>Methods: </strong>We performed phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants. We interrogated MagNET heart tissue data to identify genes and pathways associated with rs28374544. We then overexpressed FOG2S657G in a cardiomyocyte cell line and assessed the effects on cardiac metabolism and paracrine angiogenic signaling.</p><p><strong>Results: </strong>We identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Using phenome-wide association studies and deep cardiac phenotyping through the Electronic Health Record in individuals with FOG2 coding variants, we identified an association between rs28374544 (A1969G, p.S657G) and CMVD. Individuals carrying the S657G variant, almost all of African ancestry, had increased chest pain, a smaller burden of obstructive coronary artery disease, and altered coronary blood flow. Differential gene and pathway analysis using several genomic data sets showed that carriers of S657G have increased expression of genes involved in angiogenesis, glycolysis, and the HIF (hypoxia-inducible factor) pathway. In vitro functional studies show that compared with the FOG2 wild-type protein, the FOG2^S657G variant protein promotes angiogenic gene expression and angiogenesis while decreasing oxygen consumption rate.</p><p><strong>Conclusions: </strong>A common functional coding variant in FOG2, S657G, is associated with CMVD in humans. Altered angiogenic gene expression, regulated in part by FOG2, may contribute to CMVD.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005342"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13102351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>ROBO2</i> Variants Associated With Atrial Septal Defect Define a Novel Regulatory Element.","authors":"Seong Won Kim, Michael Parfenov, Laura Rodriguez-Murillo, David A Conner, Arun Sharma, Inga Peter, Feng Xiao, Olivia Layton, Angela Tai, Tarsha Ward, Lauren K Wasson, Joshua M Gorham, Erica Mazaika, Valentina N Lagomarsino, Tracy L Young-Pearse, Elizabeth Goldmuntz, Hiroko Wakimoto, A J Agopian, David M McKean, Steven R DePalma, William T Pu, Christine E Seidman, Bruce D Gelb, Jonathan G Seidman","doi":"10.1161/CIRCGEN.124.004918","DOIUrl":"10.1161/CIRCGEN.124.004918","url":null,"abstract":"<p><strong>Background: </strong>Atrial septal defects (ASDs) are a prevalent type of congenital heart disease. Previous GWAS (Genome-Wide Association Studies) have identified common variants associated with ASDs, though their mechanisms remain unknown. We aimed to expand insights into the architecture of common variants associated with ASD risk and elucidate functional mechanisms.</p><p><strong>Methods: </strong>We conducted a GWAS using isolated ASD cases and healthy controls and replicated findings in an independent cohort. We examined epigenetic marks within this ASD locus in human induced pluripotent stem cell-derived cardiomyocytes and fetal human hearts. We characterized the consequences of deletions introduced by CRISPR-Cas9 mutagenesis of human induced pluripotent stem cells to assess the effect on downstream gene expression. In addition, we investigated the 3-dimensional genome architecture of the locus using chromosome conformation capture sequencing.</p><p><strong>Results: </strong>We identified a novel ASD locus on chromosome 3p12.3 encompassing the <i>ROBO2</i> gene, which encodes the Roundabout guidance receptor 2 for Slit ligands. This locus includes 15 common single nucleotide polymorphisms, an enhancer, and a CCCTC-binding factor (CTCF)-binding site. Deletions of varying lengths within the ASD-associated locus in human induced pluripotent stem cell-derived cardiomyocytes reduced <i>ROBO2</i> expression and dysregulated the expression of extracellular matrix genes. Chromosome conformation capture sequencing indicated that this region physically interacts with the <i>ROBO2</i> promoter and demonstrates that the CTCF-binding site is essential for this contact.</p><p><strong>Conclusions: </strong>Novel common single nucleotide polymorphisms in regulatory elements controlling <i>ROBO2</i> transcription contribute to risk for ASDs. These data infer key roles for the Roundabout guidance receptor 2 and Slit ligands in embryogenic development and maturation of the atrial septa.</p>","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e004918"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13034621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of the <i>ICAM1</i> p.K56M HFpEF Risk Variant With Pericardial Adiposity and the Inflammatory Proteome.","authors":"Anushree Aneja, Kasen L Culler, Jingzhong Ding, Kent D Taylor, Sanjiv J Shah, Laura Rasmussen-Torvik, Ravi B Patel","doi":"10.1161/CIRCGEN.125.005475","DOIUrl":"10.1161/CIRCGEN.125.005475","url":null,"abstract":"","PeriodicalId":10326,"journal":{"name":"Circulation: Genomic and Precision Medicine","volume":" ","pages":"e005475"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13078727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147626412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}