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HomeCirculation ResearchVol. 130, No. 2In This Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published20 Jan 2022https://doi.org/10.1161/RES.0000000000000527Circulation Research. 2022;130:163is related toWnt5a Promotes Lysosomal Cholesterol Egress and Protects Against AtherosclerosisDevelopment and Validation of a Long-Term Incident Heart Failure Risk ModelCommon Genetic Variants Contribute to Risk of Transposition of the Great ArteriesCommon Genetic Variants Contribute to Risk of Transposition of the Great Arteries (p 166)Škorić-Milosavljević et al identify a risk locus for dextro-transposition of the great arteries.Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect in which the plumbing of the two major outflows—the aorta and pulmonary artery—are switched and thus the majority of the body is deprived of oxygen. While specific genetic mutations have been identified in certain cases of D-TGA, in most cases the underlying cause is unclear. Škorić-Milosavljević and colleagues have therefore undertaken a genome-wide association study (GWAS) to search for loci conferring D-TGA risk. In a study of more than 5 million single nucleotide polymorphisms in the genomes of 1,237 D-TGA patients and 3,711 controls, the team identified an associated locus at chromosome position 3p14.3 containing an apparent regulatory element. Since the element was conserved in the mouse genome, the team performed functional studies showing that it bound transcription factor TBX20 and suppressed expression of nearby gene, Wnt5a, which encodes a heart development factor. Notably, both TBX20 and WNT5A have been previously implicated in development of the heart’s outflow tract. Together, the findings not only provide insight into the pathology of D-TGA, but also offer a basis for possible genetic counseling of D-TGA affected families.Download figureDownload PowerPointWnt5a Promotes Lysosomal Cholesterol Egress and Protects Against Atherosclerosis (p 184)Awan et al examine Wnt5a’s lesser-known role in cholesterol homeostasis.It is well established that signaling via the Wnt family of proteins drives all manner of developmental processes including cell fate determination, proliferation and migration. Recently however, Wnt signaling has also been implicated in lipid homeostasis. Mutations that impair Wnt signaling have been shown to cause hyperlipidemia in mice and humans with Wnt signaling activity being inversely correlated with atherosclerosis severity. Because the protein Wnt5a in particular has been shown to inhibit cellular cholesterol accumulation, Awan and colleagues investigated the role of this Wnt protein in mice and human cells. Mice whose vascular smooth muscle cells (VSMCs) lacked Wnt5a developed more severe atherosclerosis compared with control animals, the team showed, while human VSMCs lacking Wnt5a accumulated far greater amounts of cholesterol in the lysosomes than did cells with normal levels of Wnt5a. The team’s further cellular analyses showed that Wnt5a normally associates with lysosomes where it promotes the catabolism of lysosomal cholesterol (via activation of lysosomal lipase) and promotes cholesterol egress via the endoplasmic reticulum. In revealing how cholesterol is trafficked by Wnt5a, the findings may help to inform future cholesterol regulating treatments.Download figureDownload PowerPointDevelopment and Validation of a Long-Term Incident Heart Failure Risk Model (p 200)Khan et al develop an equation for calculating an individual’s long-term risk of heart failure.In the US, heart failure (HF) contributes to approximately 1.2 million hospitalizations and 300,000 deaths annually with an estimated healthcare cost of over $10 billion. With both the incidence rates and costs expected to rise, a method for predicting individuals’ HF risk would enable preventative interventions, such as diet and blood pressure treatments, to be initiated early thus prolonging the number of healthy years. To develop such a prediction tool, Khan and colleagues studied decades of health data on 24,838 individuals collected as part of five separate long-running National Heart Lung and Blood Institute (NHLBI) studies. The individuals included in the model development were, at baseline, aged between 20 and 59 with no cardiovascular disease diagnosis. Analysis of their body mass indices, blood pressures, total cholesterol levels, high-density lipoprotein levels, smoking statuses, diabetes diagnoses and other cardiovascular health data over several decades enabled the team to develop an equation for predicting an individual’s likelihood of developing HF in the next 30 years. The hope is, such personalized risk estimates will help guide patient-doctor discussions regarding cardiovascular health, lifestyle choices and medical interventions, say the team.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesWnt5a Promotes Lysosomal Cholesterol Egress and Protects Against AtherosclerosisSara Awan, et al. Circulation Research. 2022;130:184-199Development and Validation of a Long-Term Incident Heart Failure Risk ModelSadiya S. Khan, et al. Circulation Research. 2022;130:200-209Common Genetic Variants Contribute to Risk of Transposition of the Great ArteriesDoris Škorić-Milosavljević, et al. Circulation Research. 2022;130:166-180 January 21, 2022Vol 130, Issue 2 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000527 Originally publishedJanuary 20, 2022 PDF download Advertisement