Atherosclerotic Aortic Calcification-Associated Polymorphism in HDAC9 and Associations with Mortality, Cardiovascular Disease, and Kidney Disease.

Johan Ärnlöv,Christoph Nowak,Douglas F Dluzen

doi:10.1016/j.isci.2020.101253

Atherosclerotic Aortic Calcification-Associated Polymorphism in HDAC9 and Associations with Mortality, Cardiovascular Disease, and Kidney Disease.

Johan Ärnlöv, Christoph Nowak + Show 1 more

Open Access

https://doi.org/10.1016/j.isci.2020.101253

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Abstract

SummaryHistone 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. Our objective was to assess associations between abdominal aortic calcification-associated genetic variation in HDAC9 and VSMC-associated phenotypes. In this prospective population study of 335,146 adults enrolled in the UK Biobank, the abdominal aortic calcification-associated risk allele of a genetic variant in HDAC9 was associated with increased risk of systolic hypertension, non-ST segment elevation myocardial infarction, and ischemic stroke. There was a suggestive protective association with kidney disease outcomes that did not reach experiment-wise significance. These genetic results lend further support for HDAC9 as a potential therapeutic target for arterial stenotic and calcific disease.

Highlights

In a recent translational genomics study, Malhotra et al (2019) identified the first genetic risk locus for abdominal aortic calcification (AAC) in Histone deacetylase 9 (HDAC9) on chromosome 7, which encodes histone deacetylase 9 (HDAC9), a coregulator of gene transcription
Our objective was to assess associations between abdominal aortic calcification-associated genetic variation in HDAC9 and vascular smooth muscle cell (VSMC)-associated phenotypes. In this prospective population study of 335,146 adults enrolled in the UK Biobank, the abdominal aortic calcification-associated risk allele of a genetic variant in HDAC9 was associated with increased risk of systolic hypertension, non-ST segment elevation myocardial infarction, and ischemic stroke
Among 335,146 participants, the AAC-associated single nucleotide polymorphism rs57301765 was genotyped in 332,425 persons (99.19%, 53.7% women, age 56.9 G 8.0 years, 10.1% smokers)

Summary

Introduction

In a recent translational genomics study, Malhotra et al (2019) identified the first genetic risk locus for abdominal aortic calcification (AAC) in HDAC9 on chromosome 7, which encodes histone deacetylase 9 (HDAC9), a coregulator of gene transcription. A separate study found that HDAC9 inhibition in mice reduced arterial neointimal formation and improved stenotic disease (Lino Cardenas et al, 2019) These findings suggest HDAC9 as a potential drug target for VSMC-associated cardiovascular disease. The results obtained by Malhotra et al (2019) demonstrate HDAC9’s role in altering VSMC phenotype, and associations with myocardial infarction, ischemic stroke, and pulse pressure have been reported (Traylor et al, 2012; Bellenguez et al, 2012; Malik et al, 2016, 2017; Nikpay et al, 2015; Kato et al, 2015) It is uncertain whether HDAC9 is implicated in other VSMC-driven diseases. We analyzed a population sample of 335,146 adults to assess the role of HDAC9 in mortality and VSMC-driven cardiovascular and renal pathology

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