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HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype

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Author(s): Rajeev Malhotra ¹ ^, ² ^, ³⁵ , Andreas C. Mauer ¹ , Christian L. Lino Cardenas ¹ ^, ² , Xiuqing Guo ³ , Jie Yao ³ , Xiaoling Zhang ⁴ ^, ⁵ , Florian Wunderer ⁶ ^, ⁷ , Albert V. Smith ⁸ ^, ⁹ , Quenna Wong ¹⁰ , Sonali Pechlivanis ¹¹ , Shih-Jen Hwang ⁴ ^, ¹² , Judy Wang ¹³ , Lingyi Lu ¹⁴ , Christopher J. Nicholson ¹ , Georgia Shelton ¹ , Mary D. Buswell ¹ , Hanna J. Barnes ¹ , Haakon H. Sigurslid ¹ , Charles Slocum ¹ , Caitlin O’Rourke ¹ , David K. Rhee ¹ ^, ² , Aranya Bagchi ² ^, ⁶ , Sagar U. Nigwekar ² ^, ¹⁵ , Emmanuel S. Buys ² ^, ⁶ , Catherine Y. Campbell ¹⁶ , Tamara Harris ¹⁷ , Matthew Budoff ¹⁸ , Michael H. Criqui ¹⁹ , Jerome I. Rotter ³ , Andrew D. Johnson ⁴ ^, ¹² , Ci Song ⁴ ^, ¹² ^, ²⁰ , Nora Franceschini ²¹ , Stephanie Debette ²² , Udo Hoffmann ² ^, ²³ , Hagen Kälsch ²⁴ ^, ²⁵ , Markus M. Nöthen ²⁶ ^, ²⁷ , Sigurdur Sigurdsson ⁸ , Barry I. Freedman ¹⁴ , Donald W. Bowden ¹⁴ , Karl-Heinz Jöckel ¹¹ , Susanne Moebus ¹¹ ^, ²⁸ , Raimund Erbel ¹¹ , Mary F. Feitosa ¹³ , Vilmundur Gudnason ⁸ ^, ²⁹ , George Thanassoulis ⁴ ^, ³⁰ , Warren M. Zapol ² ^, ⁶ , Mark E. Lindsay ¹ ^, ² , Donald B. Bloch ² ^, ⁶ ^, ³¹ ^, ³⁴ , Wendy S. Post ³² ^, ³⁴ , Christopher J. O’Donnell ¹ ^, ⁴ ^, ³³ ^, ³⁴ ^, ³⁵

Publication date (Electronic): 28 October 2019

Journal: Nature genetics

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Abstract

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine single nucleotide polymorphisms (SNPs) associated with the extent of abdominal (AAC, n = 9,417) or descending thoracic (TAC, n = 8,422) aortic calcification. Two genetic loci, HDAC9 and RAP1GAP, were associated with AAC at a genome-wide level ( P < 5.0 × 10 ⁻⁸). No SNPs were associated with TAC at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells (HASMCs) promoted calcification and reduced contractility, while inhibition of HDAC9 in HASMCs inhibited calcification and enhanced cell contractility. In matrix Gla protein (MGP)-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 novel role for HDAC9 in the development of vascular calcification.

Editorial summary

Genome-wide analyses identify variants near HDAC9 associated with abdominal aortic calcification and other cardiovascular phenotypes. Functional work shows that HDAC9 promotes an osteogenic vascular smooth muscle cell phenotype, enhancing calcification and reducing contractility.

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Most cited references 43

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Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

P. Chomczynski, N Sacchi (1987)

A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.

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Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.

Philip Greenland, Laurie LaBree, Stanley Azen … (2004)

Guidelines advise that all adults undergo coronary heart disease (CHD) risk assessment to guide preventive treatment intensity. Although the Framingham Risk Score (FRS) is often recommended for this, it has been suggested that risk assessment may be improved by additional tests such as coronary artery calcium scoring (CACS). To determine whether CACS assessment combined with FRS in asymptomatic adults provides prognostic information superior to either method alone and whether the combined approach can more accurately guide primary preventive strategies in patients with CHD risk factors. Prospective observational population-based study, of 1461 asymptomatic adults with coronary risk factors. Participants with at least 1 coronary risk factor (>45 years) underwent computed tomography (CT) examination, were screened between 1990-1992, were contacted yearly for up to 8.5 years after CT scan, and were assessed for CHD. This analysis included 1312 participants with CACS results; excluded were 269 participants with diabetes and 14 participants with either missing data or had a coronary event before CACS was performed. Nonfatal myocardial infarction (MI) or CHD death. During a median of 7.0 years of follow-up, 84 patients experienced MI or CHD death; 70 patients died of any cause. There were 291 (28%) participants with an FRS of more than 20% and 221 (21%) with a CACS of more than 300. Compared with an FRS of less than 10%, an FRS of more than 20% predicted the risk of MI or CHD death (hazard ratio [HR], 14.3; 95% confidence interval [CI]; 2.0-104; P =.009). Compared with a CACS of zero, a CACS of more than 300 was predictive (HR, 3.9; 95% CI, 2.1-7.3; P<.001). Across categories of FRS, CACS was predictive of risk among patients with an FRS higher than 10% (P<.001) but not with an FRS less than 10%. These data support the hypothesis that high CACS can modify predicted risk obtained from FRS alone, especially among patients in the intermediate-risk category in whom clinical decision making is most uncertain.

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Genetic associations with valvular calcification and aortic stenosis.

George Thanassoulis, Catherine Y Campbell, David S Owens … (2013)

Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 17 September 2019

Publication date (Electronic): 28 October 2019

Publication date (Print): November 2019

Publication date PMC-release: 28 April 2020

Volume: 51

Issue: 11

Pages: 1580-1587

Affiliations

[1 ]Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

[2 ]Harvard Medical School, Boston, MA, USA

[3 ]Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA

[4 ]National Heart Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

[5 ]Departments of Medicine (Biomedical Genetics) and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA

[6 ]Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA

[7 ]Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany

[8 ]Icelandic Heart Association, Kopavogur, Iceland

[9 ]Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

[10 ]Department of Biostatistics, University of Washington, Seattle, WA, USA

[11 ]Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany

[12 ]National Heart, Lung and Blood Institute, Population Sciences Branch, Division of Intramural Research, Bethesda, MD, USA

[13 ]Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA

[14 ]Wake Forest School of Medicine, Winston-Salem, NC, USA

[15 ]Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

[16 ]Mid-Atlantic Permanente Medical Group, Rockville, MD, USA

[17 ]National Institute on Aging, Bethesda, MD, USA

[18 ]Division of Cardiology, Department of Medicine and Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA

[19 ]Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA

[20 ]Deptartment of Medical Sciences, Uppsala University, Uppsala, Sweden

[21 ]Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

[22 ]Inserm U1219, University of Bordeaux, and Department of Neurology at Bordeaux University Hospital, Bordeaux, France

[23 ]Department of Radiology, Massachusetts General Hospital, Boston, MA, USA

[24 ]Department of Cardiology, Alfried Krupp Krankenhaus, Essen, Germany

[25 ]Witten/Herdecke University, Witten, Germany

[26 ]Institute of Human Genetics, University of Bonn, Bonn, Germany

[27 ]Department of Genomics, Life & Brain GmbH, University of Bonn, Bonn, Germany

[28 ]Centre for Urban Epidemiology, University Hospital Essen, Essen, Germany

[29 ]Faculty of Medicine, University of Iceland, Reykjavik, Iceland

[30 ]Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada

[31 ]Division of Rheumatology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

[32 ]Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA

[33 ]US Department of Veterans Affairs, Boston, MA, USA

[34 ]These authors contributed equally to this work.

Author notes

Author Contributions

Concept and design of genome-wide association study: R.M., A.C.M., X.G., J.Y., C.Y.C., W.S.P., C.J.O.

Cohort-based phenotype and genotype acquisition: A.V.S., Q.W., S.P., S.-J.H., J.W., L.L., C.Y.C., T.H., M.B., M.H.C., J.I.R., A.D.J., C. Song, N.F., S.D., U.H., H.K., M.M.N., S.S., B.I.F., D.W.B., K.-H.J., S.M., R.E., M.F.F., V.G., G.T., W.S.P., C.J.O.

Meta-analysis and sQTL analysis: R.M., A.C.M., X.G., J.Y., X.Z., W.S.P., C.J.O.

Concept and design of cell-based assays and in vivo studies: R.M.

Acquisition, analysis, or interpretation of data in cell-based assays and in vivo studies: R.M., C.L.L.C., F.W., C.J.N., G.S., M.D.B., H.J.B., C. Slocum, H.H.S., C.O., D.K.R., A.B., S.U.N., E.S.B., W.M.Z., M.E.L., D.B.B.

Drafting of the manuscript: R.M., A.C.M., C.J.O.

Critical revision of the manuscript for important intellectual content: all authors

Approval of content of manuscript: all authors

[35 ] These authors jointly directed this work. Correspondence should be addressed to R.M. ( rmalhotra@ 123456mgh.harvard.edu ) or C.J.O. ( Christopher.ODonnell@ 123456va.gov ).

Article

Manuscript ID: NIHMS1540170

DOI: 10.1038/s41588-019-0514-8

PMC ID: 6858575

PubMed ID: 31659325

SO-VID: 26cb28c3-78b7-4b03-84fe-c7adf916d5ca

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