Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification

Paul S. de Vries, Matthew P. Conomos, Kuldeep Singh, Christopher J. Nicholson, Deepti Jain, Natalie R. Hasbani, Wanlin Jiang, Sujin Lee, Christian L. Lino Cardenas, Sharon M. Lutz, Doris Wong, Xiuqing Guo, Jie Yao, Erica P. Young, Catherine Tcheandjieu, Austin T. Hilliard, Joshua C. Bis, Lawrence F. Bielak, Michael R. Brown, Shaila MusharoffShoa L. Clarke, James G. Terry, Nicholette D. Palmer, Lisa R. Yanek, Huichun Xu, Nancy Heard-Costa, Jennifer Wessel, Margaret Sunitha Selvaraj, Rebecca H. Li, Xiao Sun, Adam W. Turner, Adrienne M. Stilp, Alyna Khan, Anne B. Newman, Asif Rasheed, Barry I. Freedman, Brian G. Kral, Caitlin P. McHugh, Chani Hodonsky, Danish Saleheen, David M. Herrington, David R. Jacobs, Deborah A. Nickerson, Eric Boerwinkle, Fei Fei Wang, Gerardo Heiss, Goo Jun, Greg L. Kinney, Haakon H. Sigurslid, Harsha Vardhan Doddapaneni, Ira M. Hall, Isabela M. Bensenor, Jai Broome, James D. Crapo, James G. Wilson, Jennifer A. Smith, John Blangero, Jose D. Vargas, Jose Verdezoto Mosquera, Joshua D. Smith, Karine A. Viaud-Martinez, Kathleen A. Ryan, Kendra A. Young, Kent D. Taylor, Leslie A. Lange, Leslie S. Emery, Marcio S. Bittencourt, Matthew J. Budoff, May E. Montasser, Miao Yu, Michael C. Mahaney, Mohammed S. Mahamdeh, Myriam Fornage, Nora Franceschini, Paulo A. Lotufo, Pradeep Natarajan, Quenna Wong, Rasika A. Mathias, Richard A. Gibbs, Ron Do, Roxana Mehran, Russell P. Tracy, Ryan W. Kim, Sarah C. Nelson, Scott M. Damrauer, Sharon L.R. Kardia, Stephen S. Rich, Valentin Fuster, Valerio Napolioni, Wei Zhao, Wenjie Tian, Xianyong Yin, Yuan I. Min, Alisa K. Manning, Gina Peloso, Tanika N. Kelly, Christopher J. O’Donnell, Alanna C. Morrison, Joanne E. Curran, Warren M. Zapol, Donald W. Bowden, Lewis C. Becker, Adolfo Correa, Braxton D. Mitchell, Bruce M. Psaty, John Jeffrey Carr, Alexandre C. Pereira, Themistocles L. Assimes, Nathan O. Stitziel, John E. Hokanson, Cecelia A. Laurie, Jerome I. Rotter, Ramachandran S. Vasan, Wendy S. Post, Patricia A. Peyser, Clint L. Miller, Rajeev Malhotra

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Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification and a potential drug target for vascular calcific disease.

Original languageEnglish
Pages (from-to)1159-1172
Number of pages14
JournalNature Cardiovascular Research
Issue number12
StatePublished - Dec 2023


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