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

TitleWhole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.
Publication TypeJournal Article
Year of Publication2023
Authorsde Vries, PS, Conomos, MP, Singh, K, Nicholson, CJ, Jain, D, Hasbani, NR, Jiang, W, Lee, S, Cardenas, CLLino, 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, MSunitha, 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, FFei, Heiss, G, Jun, G, Kinney, GL, Sigurslid, HH, Doddapaneni, H, Hall, IM, Bensenor, IM, Broome, J, Crapo, JD, Wilson, JG, Smith, JA, Blangero, J, Vargas, JD, Mosquera, JVerdezoto, 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, Y-I, 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, JJeffrey, Pereira, AC, Assimes, TL, Stitziel, NO, Hokanson, JE, Laurie, CA, Rotter, JI, Vasan, RS, Post, WS, Peyser, PA, Miller, CL, Malhotra, R
JournalNat Cardiovasc Res
Volume2
Issue12
Pagination1159-1172
Date Published2023 Dec
ISSN2731-0590
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 (GWAS) 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 ( and ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of and in human vascular smooth muscle cells (VSMCs) demonstrate that 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 with reduced CAC is likely explained by reduced 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.

DOI10.1038/s44161-023-00375-y
Alternate JournalNat Cardiovasc Res
PubMed ID38817323
PubMed Central IDPMC11138106
Grant ListR01 HL120393 / HL / NHLBI NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL162928 / HL / NHLBI NIH HHS / United States
R01 HL146860 / HL / NHLBI NIH HHS / United States
R01 HL164577 / HL / NHLBI NIH HHS / United States
R01 HL148239 / HL / NHLBI NIH HHS / United States
U01 HL137162 / HL / NHLBI NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 HL142809 / HL / NHLBI NIH HHS / United States
R01 HL159514 / HL / NHLBI NIH HHS / United States
R01 HL142711 / HL / NHLBI NIH HHS / United States