Sepiede Azghandi1, Caroline Prell1, Sander W van der Laan1, Manuela Schneider1, Rainer Malik1, Kerstin Berer1, Norbert Gerdes1, Gerard Pasterkamp1, Christian Weber1, Christof Haffner1, Martin Dichgans2. 1. From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany (S.A., C.P., M.S., R.M., C.H., M.D.); Divisions Heart and Lungs and Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands (S.W.v.d.L., G.P.); Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany (K.B.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (N.G., C.W.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.). 2. From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany (S.A., C.P., M.S., R.M., C.H., M.D.); Divisions Heart and Lungs and Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands (S.W.v.d.L., G.P.); Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried, Germany (K.B.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (N.G., C.W.); and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M.D.). martin.dichgans@med.uni-muenchen.de.
Abstract
BACKGROUND AND PURPOSE: Recent genome-wide association studies identified the histone deacetylase 9 (HDAC9) gene region as a major risk locus for large-vessel stroke and coronary artery disease. However, the mechanisms linking variants at this locus to vascular risk are poorly understood. In this study, we investigated the candidacy and directionality of HDAC9 in atherosclerosis and analyzed associations between risk alleles at 7p21.1 and plaque characteristics. METHODS: Allele-dependent expression of HDAC9 was analyzed in human peripheral blood mononuclear cells of healthy donors. Effects of HDAC9 deficiency on atherosclerotic plaques were investigated in 18- and 28-week-old ApoE(-/-) mice by histology and immunohistochemistry. We further performed detailed plaque phenotyping and genotyping of rs2107595, the lead single-nucleotide polymorphism for large-vessel stroke, in carotid endarterectomy samples of 1858 subjects from the Athero-Express study. RESULTS: Gene expression studies in peripheral blood mononuclear cells revealed increased mRNA levels of HDAC9 but not of neighboring genes (TWIST1/FERD3L) in risk allele carriers of rs2107595. Compared with HDAC9(+/+)ApoE(-/-) mice, HDAC9(-/-)ApoE(-/-) mice exhibited markedly reduced lesion sizes throughout atherosclerotic aortas and significantly less advanced lesions. The proportion of Mac3-positive macrophages was higher in plaques from HDAC9(-/-)ApoE(-/-) mice, but this was largely because of a lower proportion of advanced lesions. Analysis of human atherosclerotic plaques revealed no association between rs2107595 and specific plaque characteristics. CONCLUSIONS: Our results suggest that HDAC9 represents the disease-relevant gene at the stroke and coronary artery disease risk locus on 7p21.1, and that risk alleles in this region mediate their effects through increased HDAC9 expression. Targeted inhibition of HDAC9 might be a viable strategy to prevent atherosclerosis.
BACKGROUND AND PURPOSE: Recent genome-wide association studies identified the histone deacetylase 9 (HDAC9) gene region as a major risk locus for large-vessel stroke and coronary artery disease. However, the mechanisms linking variants at this locus to vascular risk are poorly understood. In this study, we investigated the candidacy and directionality of HDAC9 in atherosclerosis and analyzed associations between risk alleles at 7p21.1 and plaque characteristics. METHODS: Allele-dependent expression of HDAC9 was analyzed in human peripheral blood mononuclear cells of healthy donors. Effects of HDAC9 deficiency on atherosclerotic plaques were investigated in 18- and 28-week-old ApoE(-/-) mice by histology and immunohistochemistry. We further performed detailed plaque phenotyping and genotyping of rs2107595, the lead single-nucleotide polymorphism for large-vessel stroke, in carotid endarterectomy samples of 1858 subjects from the Athero-Express study. RESULTS: Gene expression studies in peripheral blood mononuclear cells revealed increased mRNA levels of HDAC9 but not of neighboring genes (TWIST1/FERD3L) in risk allele carriers of rs2107595. Compared with HDAC9(+/+)ApoE(-/-) mice, HDAC9(-/-)ApoE(-/-) mice exhibited markedly reduced lesion sizes throughout atherosclerotic aortas and significantly less advanced lesions. The proportion of Mac3-positive macrophages was higher in plaques from HDAC9(-/-)ApoE(-/-) mice, but this was largely because of a lower proportion of advanced lesions. Analysis of humanatherosclerotic plaques revealed no association between rs2107595 and specific plaque characteristics. CONCLUSIONS: Our results suggest that HDAC9 represents the disease-relevant gene at the stroke and coronary artery disease risk locus on 7p21.1, and that risk alleles in this region mediate their effects through increased HDAC9 expression. Targeted inhibition of HDAC9 might be a viable strategy to prevent atherosclerosis.
Authors: Rainer Malik; Therese Dau; Maria Gonik; Anirudh Sivakumar; Daniel J Deredge; Evgeniia V Edeleva; Jessica Götzfried; Sander W van der Laan; Gerard Pasterkamp; Nathalie Beaufort; Susana Seixas; Steve Bevan; Lisa F Lincz; Elizabeth G Holliday; Annette I Burgess; Kristiina Rannikmäe; Jens Minnerup; Jennifer Kriebel; Melanie Waldenberger; Martina Müller-Nurasyid; Peter Lichtner; Danish Saleheen; Peter M Rothwell; Christopher Levi; John Attia; Cathie L M Sudlow; Dieter Braun; Hugh S Markus; Patrick L Wintrode; Klaus Berger; Dieter E Jenne; Martin Dichgans Journal: Proc Natl Acad Sci U S A Date: 2017-03-06 Impact factor: 11.205
Authors: Anurag Verma; Anastasia Lucas; Shefali S Verma; Yu Zhang; Navya Josyula; Anqa Khan; Dustin N Hartzel; Daniel R Lavage; Joseph Leader; Marylyn D Ritchie; Sarah A Pendergrass Journal: Am J Hum Genet Date: 2018-03-29 Impact factor: 11.025