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

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.