Association between Atherosclerotic Aortic Calcification-Associated Genetic Variation in <i>HDAC9</i> with Mortality, Cardiovascular Disease and Kidney Disease

Abstract

Importance: Histone deacetylase 9 (HDAC9) has recently been demonstrated as a key regulator of vascular smooth muscle cell (VSMC) phenotype and is associated with abdominal aortic calcification, myocardial infarction and ischemic stroke. It is uncertain whether HDAC9 is also implicated in other VSMC-driven diseases. Objective: To investigate associations between abdominal aortic calcification-associated genetic variation in HDAC9 and VSMC-associated phenotypes. Design: Prospective population study.Setting: UK Biobank.Participants: 335,146 European, non-related person aged 40-69 years (mean 57±8 years, 54% women). Main outcomes: Blood pressure, heart rate, hypertension, myocardial infarction, stroke, arterial aneurysm, heart failure, glomerular filtration rate, albuminuria, end-stage renal disease, all-cause and cardiovascular mortality, HbA1c, diabetes, serum lipids, body mass index, and smoking. Results: We used the aortic calcification-raising A-allele of rs57301765 in HDAC9 as a genetic instrumental variable to query the long-term effects of HDAC9 variation. At the Bonferroni significance level, rs57301765 was associated with systolic blood pressure (effect per added risk allele in standard deviation units, 0.022; 95% CI, 0.016-0.029, P=1.71×10-11), pulse pressure (0.035; 95% CI, 0.028-0.041, P=5.76×10-27), hypertension (odds ratio, OR, 1.04; 95% CI, 1.02-1.05, P=1.26×10-6), myocardial infarction (OR, 1.08; 95% CI, 1.04-1.12, P=1.72×10-5, driven by non-ST segment elevation myocardial infarction, OR, 1.11; 95% CI, 1.04-1.17, P=0.001), and ischemic stroke (OR, 1.14; 95% CI, 1.07-1.22, P=6.29×10-5). There was a suggestive protective association with kidney disease outcomes that, however, did not reach experiment-wise significance. Look-ups in public genome-wide association study results concur with our findings for cardiovascular outcomes. Conclusions and Relevance: The genetic results in our study lend further support for HDAC9 as a key determinant of VSMC-associated cardiovascular pathology and its potential as a therapeutic target for arterial stenotic and calcific disease.