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 Musharoff; Shoa 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

doi:10.1038/s44161-023-00375-y

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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Abstract

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 language	English (US)
Pages (from-to)	1159-1172
Number of pages	14
Journal	Nature Cardiovascular Research
Volume	2
Issue number	12
DOIs	https://doi.org/10.1038/s44161-023-00375-y
State	Published - Dec 2023

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© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

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de Vries, P. S., Conomos, M. P., Singh, K., Nicholson, C. J., Jain, D., Hasbani, N. R., Jiang, W., Lee, S., Lino Cardenas, C. L., Lutz, S. M., Wong, D., Guo, X., Yao, J., Young, E. P., Tcheandjieu, C., Hilliard, A. T., Bis, J. C., Bielak, L. F., Brown, M. R., ... Malhotra, R. (2023). Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification. Nature Cardiovascular Research, 2(12), 1159-1172. https://doi.org/10.1038/s44161-023-00375-y

de Vries, PS, Conomos, MP, Singh, K, Nicholson, CJ, Jain, D, Hasbani, NR, Jiang, W, Lee, S, Lino Cardenas, CL, Lutz, SM, Wong, D, Guo, X, Yao, J, Young, EP, Tcheandjieu, C, Hilliard, AT, Bis, JC, Bielak, LF, Brown, MR, Musharoff, S, Clarke, SL, Terry, JG, Palmer, ND, Yanek, LR, Xu, H, Heard-Costa, N, Wessel, J, Selvaraj, MS, Li, RH, Sun, X, Turner, AW, Stilp, AM, Khan, A, Newman, AB, Rasheed, A, Freedman, BI, Kral, BG, McHugh, CP, Hodonsky, C, Saleheen, D, Herrington, DM, Jacobs, DR, Nickerson, DA, Boerwinkle, E, Wang, FF, Heiss, G, Jun, G, Kinney, GL, Sigurslid, HH, Doddapaneni, HV, Hall, IM, Bensenor, IM, Broome, J, Crapo, JD, Wilson, JG, Smith, JA, Blangero, J, Vargas, JD, Mosquera, JV, Smith, JD, Viaud-Martinez, KA, Ryan, KA, Young, KA, Taylor, KD, Lange, LA, Emery, LS, Bittencourt, MS, Budoff, MJ, Montasser, ME, Yu, M, Mahaney, MC, Mahamdeh, MS, Fornage, M, Franceschini, N, Lotufo, PA, Natarajan, P, Wong, Q, Mathias, RA, Gibbs, RA, Do, R, Mehran, R, Tracy, RP, Kim, RW, Nelson, SC, Damrauer, SM, Kardia, SLR, Rich, SS, Fuster, V, Napolioni, V, Zhao, W, Tian, W, Yin, X, Min, YI, Manning, AK, Peloso, G, Kelly, TN, O’Donnell, CJ, Morrison, AC, Curran, JE, Zapol, WM, Bowden, DW, Becker, LC, Correa, A, Mitchell, BD, Psaty, BM, Carr, JJ, Pereira, AC, Assimes, TL, Stitziel, NO, Hokanson, JE, Laurie, CA, Rotter, JI, Vasan, RS, Post, WS, Peyser, PA, Miller, CL & Malhotra, R 2023, 'Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification', Nature Cardiovascular Research, vol. 2, no. 12, pp. 1159-1172. https://doi.org/10.1038/s44161-023-00375-y

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abstract = "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.",

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note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s44161-023-00375-y",

language = "English (US)",

volume = "2",

pages = "1159--1172",

journal = "Nature Cardiovascular Research",

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T1 - Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification

AU - de Vries, Paul S.

AU - Conomos, Matthew P.

AU - Singh, Kuldeep

AU - Nicholson, Christopher J.

AU - Jain, Deepti

AU - Hasbani, Natalie R.

AU - Jiang, Wanlin

AU - Lee, Sujin

AU - Lino Cardenas, Christian L.

AU - Lutz, Sharon M.

AU - Wong, Doris

AU - Guo, Xiuqing

AU - Yao, Jie

AU - Young, Erica P.

AU - Tcheandjieu, Catherine

AU - Hilliard, Austin T.

AU - Bis, Joshua C.

AU - Bielak, Lawrence F.

AU - Brown, Michael R.

AU - Musharoff, Shaila

AU - Clarke, Shoa L.

AU - Terry, James G.

AU - Palmer, Nicholette D.

AU - Yanek, Lisa R.

AU - Xu, Huichun

AU - Heard-Costa, Nancy

AU - Wessel, Jennifer

AU - Selvaraj, Margaret Sunitha

AU - Li, Rebecca H.

AU - Sun, Xiao

AU - Turner, Adam W.

AU - Stilp, Adrienne M.

AU - Khan, Alyna

AU - Newman, Anne B.

AU - Rasheed, Asif

AU - Freedman, Barry I.

AU - Kral, Brian G.

AU - McHugh, Caitlin P.

AU - Hodonsky, Chani

AU - Saleheen, Danish

AU - Herrington, David M.

AU - Jacobs, David R.

AU - Nickerson, Deborah A.

AU - Boerwinkle, Eric

AU - Wang, Fei Fei

AU - Heiss, Gerardo

AU - Jun, Goo

AU - Kinney, Greg L.

AU - Sigurslid, Haakon H.

AU - Doddapaneni, Harsha Vardhan

AU - Hall, Ira M.

AU - Bensenor, Isabela M.

AU - Broome, Jai

AU - Crapo, James D.

AU - Wilson, James G.

AU - Smith, Jennifer A.

AU - Blangero, John

AU - Vargas, Jose D.

AU - Mosquera, Jose Verdezoto

AU - Smith, Joshua D.

AU - Viaud-Martinez, Karine A.

AU - Ryan, Kathleen A.

AU - Young, Kendra A.

AU - Taylor, Kent D.

AU - Lange, Leslie A.

AU - Emery, Leslie S.

AU - Bittencourt, Marcio S.

AU - Budoff, Matthew J.

AU - Montasser, May E.

AU - Yu, Miao

AU - Mahaney, Michael C.

AU - Mahamdeh, Mohammed S.

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Lotufo, Paulo A.

AU - Natarajan, Pradeep

AU - Wong, Quenna

AU - Mathias, Rasika A.

AU - Gibbs, Richard A.

AU - Do, Ron

AU - Mehran, Roxana

AU - Tracy, Russell P.

AU - Kim, Ryan W.

AU - Nelson, Sarah C.

AU - Damrauer, Scott M.

AU - Kardia, Sharon L.R.

AU - Rich, Stephen S.

AU - Fuster, Valentin

AU - Napolioni, Valerio

AU - Zhao, Wei

AU - Tian, Wenjie

AU - Yin, Xianyong

AU - Min, Yuan I.

AU - Manning, Alisa K.

AU - Peloso, Gina

AU - Kelly, Tanika N.

AU - O’Donnell, Christopher J.

AU - Morrison, Alanna C.

AU - Curran, Joanne E.

AU - Zapol, Warren M.

AU - Bowden, Donald W.

AU - Becker, Lewis C.

AU - Correa, Adolfo

AU - Mitchell, Braxton D.

AU - Psaty, Bruce M.

AU - Carr, John Jeffrey

AU - Pereira, Alexandre C.

AU - Assimes, Themistocles L.

AU - Stitziel, Nathan O.

AU - Hokanson, John E.

AU - Laurie, Cecelia A.

AU - Rotter, Jerome I.

AU - Vasan, Ramachandran S.

AU - Post, Wendy S.

AU - Peyser, Patricia A.

AU - Miller, Clint L.

AU - Malhotra, Rajeev

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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JF - Nature Cardiovascular Research

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ER -

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

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