Abstract
Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10−8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1580-1587 |
| Number of pages | 8 |
| Journal | Nature genetics |
| Volume | 51 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2019 |
ASJC Scopus subject areas
- Genetics
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HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype. / Malhotra, Rajeev; Mauer, Andreas C.; Lino Cardenas, Christian L.; Guo, Xiuqing; Yao, Jie; Zhang, Xiaoling; Wunderer, Florian; Smith, Albert V.; Wong, Quenna; Pechlivanis, Sonali; Hwang, Shih Jen; Wang, Judy; Lu, Lingyi; Nicholson, Christopher J.; Shelton, Georgia; Buswell, Mary D.; Barnes, Hanna J.; Sigurslid, Haakon H.; Slocum, Charles; Rourke, Caitlin O.; Rhee, David K.; Bagchi, Aranya; Nigwekar, Sagar U.; Buys, Emmanuel S.; Campbell, Catherine Y.; Harris, Tamara; Budoff, Matthew; Criqui, Michael H.; Rotter, Jerome I.; Johnson, Andrew D.; Song, Ci; Franceschini, Nora; Debette, Stephanie; Hoffmann, Udo; Kälsch, Hagen; Nöthen, Markus M.; Sigurdsson, Sigurdur; Freedman, Barry I.; Bowden, Donald W.; Jöckel, Karl Heinz; Moebus, Susanne; Erbel, Raimund; Feitosa, Mary F.; Gudnason, Vilmundur; Thanassoulis, George; Zapol, Warren M.; Lindsay, Mark E.; Bloch, Donald B.; Post, Wendy S.; O’Donnell, Christopher J.
In: Nature genetics, Vol. 51, No. 11, 01.11.2019, p. 1580-1587.Research output: Contribution to journal › Letter › peer-review
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TY - JOUR
T1 - HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype
AU - Malhotra, Rajeev
AU - Mauer, Andreas C.
AU - Lino Cardenas, Christian L.
AU - Guo, Xiuqing
AU - Yao, Jie
AU - Zhang, Xiaoling
AU - Wunderer, Florian
AU - Smith, Albert V.
AU - Wong, Quenna
AU - Pechlivanis, Sonali
AU - Hwang, Shih Jen
AU - Wang, Judy
AU - Lu, Lingyi
AU - Nicholson, Christopher J.
AU - Shelton, Georgia
AU - Buswell, Mary D.
AU - Barnes, Hanna J.
AU - Sigurslid, Haakon H.
AU - Slocum, Charles
AU - Rourke, Caitlin O.
AU - Rhee, David K.
AU - Bagchi, Aranya
AU - Nigwekar, Sagar U.
AU - Buys, Emmanuel S.
AU - Campbell, Catherine Y.
AU - Harris, Tamara
AU - Budoff, Matthew
AU - Criqui, Michael H.
AU - Rotter, Jerome I.
AU - Johnson, Andrew D.
AU - Song, Ci
AU - Franceschini, Nora
AU - Debette, Stephanie
AU - Hoffmann, Udo
AU - Kälsch, Hagen
AU - Nöthen, Markus M.
AU - Sigurdsson, Sigurdur
AU - Freedman, Barry I.
AU - Bowden, Donald W.
AU - Jöckel, Karl Heinz
AU - Moebus, Susanne
AU - Erbel, Raimund
AU - Feitosa, Mary F.
AU - Gudnason, Vilmundur
AU - Thanassoulis, George
AU - Zapol, Warren M.
AU - Lindsay, Mark E.
AU - Bloch, Donald B.
AU - Post, Wendy S.
AU - O’Donnell, Christopher J.
N1 - Funding Information: We acknowledge the essential role of the CHARGE Consortium in the development and support of this manuscript. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute (NHLBI), the NIH or the U. S. Department of Health and Human Services. The Framingham Heart Study was supported by the NHLBI (contract no. N01-HC-25195) and its contract with Affymetrix for genotyping services (contract No. N02-HL-6-4278). R.M. was supported by the NHLBI (grant nos. K08HL111210 and R01HL142809), the American Heart Association (grant no. 18TPA34230025), the Wild Family Foundation and the Hassenfeld Scholar Award. F.W. was supported by Deutsche Forschungsgemeinschaft (DFG; no. Wu 841/1-1). A.B. was supported by the Department of Defense Peer Reviewed Medical Research Program/Discovery Award (no. W81XWH-17-1-0058). S.U.N. was supported by the American Heart Association (grant no. 15FTF25980003). C.Song was supported by an international postdoctoral fellowship from the Swedish research council (no. 2016-00598). U.H. received research support unrelated to the current project: research grants on behalf of the institution from Kowa, MedImmune, HeartFlow, Duke University (Abbott), Oregon Health & Science University (American Hospital Association; no. 13FTF16450001), Columbia University (NIH; no. 5R01-HL109711) and NIH/NHLBI grant nos. 5K24HL113128, 5T32HL076136 and 5U01HL123339. M.E.L. was supported by the Fredman Fellowship, the Toomey Fund for Aortic Dissection Research and grant no. R01 HL130113. D.B.B. was supported by the Leducq Foundation and the National Institutes of Diabetes and Digestive and Kidney Diseases (no. 5R01DK082971). The Age, Gene/Environment Susceptibility-Reykjavik Study has been funded by National Institute on Aging (NIA) contract no. N01-AG-12100 with contributions from the National Eye Institute, National Institute on Deafness and Other Communication Disorders, NHLBI, NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and Althingi (Icelandic Parliament). MESA and the MESA SHARe project are conducted and supported by the NHLBI in collaboration with MESA investigators. MESA was supported by grant nos. R01 HL071739 and R01 HL72403, and by contract nos. HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079 and UL1-TR-001420. Funding for the SHARe genotyping was provided by NHLBI contract no. N02-HL-64278. Genotyping was performed at Affymetrix and the Broad Institute of Harvard and MIT using the Affymetrix Genome-Wide Human SNP Array 6.0. This work was also supported in part by the National Center for Advancing Translational Sciences, Clinical Translational Science Institute grant no. UL1TR001881 and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) Diabetes Research Center (DRC) grant no. DK063491 to the Southern California Diabetes Endocrinology Research Center. M.B. was supported by the NIH grant no. R01HL071739. We thank the other investigators, staff and participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www. mesa-nhlbi.org. The FamHS research was supported by NIH grant no. R01-HL-117078 from the NHLBI and grant no. R01-DK-089256 from the NIDDK. We are indebted to all the study participants and to the dedicated personnel of both the study center of the Heinz Nixdorf Recall study and the electron beam tomography scanner facilities (D. Grönemeyer and R. Seibel) as well as to the investigative group, in particular to U. Roggenbuck, U. Slomiany, E.M. Beck, A. Öffner, S. Münkel, M. Bauer, S. Schrader, R. Peter and H. Hirche. Scientific advisory board: We thank T. Meinertz (Chair), M. Blettner, C. Bode, P. J. de Feyter, B. Güntert, F. Gutzwiller, H. Heinen, O. Hess (deceased), B. Klein (deceased), H. Löwel, M. Reiser, G. Schmidt (deceased), M. Schwaiger, C. Steinmüller, T. Theorell and S.N. Willich. Criteria and end point committee: C. Bode (Chair), K. Berger, H.R. Figulla, C. Hamm, P. Hanrath, W. Köpcke, C. Weimar, A. Zeiher. Funding: We thank the Heinz Nixdorf Foundation (Chairman: M. Nixdorf; Past Chairman: G. Schmidt (deceased)), the German Ministry of Education and Science and the DFG (project nos. ER 155/6-1 and ER 155/6-2) for the generous support of this study. An additional research grant was received from Imatron, which provided the electron beam computerized tomography scanners, and GE-Imatron after the acquisition of Imatron. We acknowledge the support of the Sarstedt AG & Co. concerning laboratory equipment. We received generous support from the Ministry of Culture and Science of North Rhine-Westphalia and the Faculty of Medicine, University Duisburg-Essen for the genotyping of the Heinz Nixdorf Recall study participants. S.P. was supported by the DFG (project no. PE 2309/2-1). M.M.N. received support from the DFG (German Research Foundation) through the Transregional Collaborative Research Centre grant TRR259 (subproject B07 ”GUARD–Genes Underlying AoRtic valve Disease“; project number 426128588) and is a member of the Excellence Cluster ImmunoSensation2, which is funded by the DFG under Germany’s Excellence Strategy–EXC2151 (project number 390873048). Technical support for the imputation of the Heinz Nixdorf Recall Study data on the Supercomputer Cray XT6m was provided by the Center for Information and Media Services, University of Duisburg-Essen. The AA-DHS was supported by grant nos. R01-DK-071891 from the NIDDK, RO1-HL-67348 from the NHLBI and General Clinical Research Center of Wake Forest School of Medicine M01-RR-07122. N.F. is supported by NIH grant nos. MD012765, DK117445 and HL140385. Publisher Copyright: © 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10−8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
AB - Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10−8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
UR - http://www.scopus.com/inward/record.url?scp=85074362319&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074362319&partnerID=8YFLogxK
U2 - 10.1038/s41588-019-0514-8
DO - 10.1038/s41588-019-0514-8
M3 - Letter
C2 - 31659325
AN - SCOPUS:85074362319
VL - 51
SP - 1580
EP - 1587
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 11
ER -