Restricted accessResearch articleFirst published online 2025
Cumulative evidence for associations between variants in the histone deacetylases genes and cardio-cerebrovascular diseases: A systematic review and meta-analysis
Background: A variety of studies have reported the associations between histone deacetylases (HDACs) genes and cardio-cerebrovascular diseases. The identification of variants in the HDACs genes and the determination of risk alleles could open novel therapeutic avenues for these diseases. This article summarized variants in HDACs genes and different sub-types of cardio-cerebrovascular diseases.
Methods: A comprehensive literature search was conducted across PubMed, Web of Science and Scopus databases to identify studies published prior to 27 June 2025. We registered this protocol in the PROSPERO database (CRD420251010100). The Venice Criteria were applied to assess the statistically significant associations identified by meta-analyses. The single-nucleotide polymorphisms were mapped to their corresponding genes, and functional annotation was conducted using the Encyclopedia of DNA Elements tool, HaploReg and the UCSC Genome browser.
Results: We finally included 34 published studies and 160 datasets to assess the associations between variants in HDAC genes and cardio-cerebrovascular diseases. Rs2107595 in HDAC 9 was the variant found to be associated with four sub-types identified by genome-wide association study or meta-analyses. Rs11984041 was related to ischemic stroke. Rs10230207 and rs2192476 were associated with intracranial aneurysm.
Conclusions:HDACs genes were associated with multiple cardio-cerebrovascular diseases. However, ethnic disparities were observed in their effects. Therefore, ethnicity-targeted treatments, including specific HDAC inhibitors, should be developed in the future.
YinCYangJFengJ, et al.Tailoring the reversible phase transition of perovskite nanofiber electrodes for high-performance and durable reversible solid oxide cells. Nanomicro Lett2025; 17: 150.
2.
HoTCSChanAHYGanesanA. Thirty years of HDAC inhibitors: 2020 insight and hindsight. J Med Chem2020; 63: 12460–12484.
3.
GilletteTG. HDAC inhibition in the heart: erasing hidden fibrosis. Circulation2021; 143: 1891–1893.
4.
KeeHJSohnISNamKI, et al.Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation2006; 113: 51–59.
5.
WallnerMEatonDMBerrettaRM, et al.HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci Transl Med2020; 12: eaay7205.
6.
Network NSG, International Stroke Genetics C. Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol2016; 15: 174–184.
7.
International Stroke Genetics C, Wellcome Trust Case Control C, BellenguezCBevanSGschwendtnerA, , et al.Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet2012; 44: 328–333.
8.
DuanLWeiLTianY, et al.Novel susceptibility loci for moyamoya disease revealed by a genome-wide association study. Stroke2018; 49: 11–18.
9.
WangZZhaoYTZhaoTC. Histone deacetylases in modulating cardiac disease and their clinical translational and therapeutic implications. Exp Biol Med (Maywood)2021; 246: 213–225.
10.
SagooGSLittleJHigginsJP. Systematic reviews of genetic association studies. Human genome epidemiology network. PLoS Med2009; 6: e28.
11.
LauJIoannidisJPSchmidCH. Quantitative synthesis in systematic reviews. Ann Intern Med1997; 127: 820–826.
12.
HigginsJPThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med2002; 21: 1539–1558.
13.
BeggCBMazumdarM. Operating characteristics of a rank correlation test for publication bias. Biometrics1994; 50: 1088–1101.
14.
EggerMDavey SmithGSchneiderM, et al.Bias in meta-analysis detected by a simple, graphical test. Br Med J1997; 315: 629–634.
15.
IoannidisJPTrikalinosTA. An exploratory test for an excess of significant findings. Clin Trials2007; 4: 245–253.
16.
IoannidisJPBoffettaPLittleJ, et al.Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol2008; 37: 120–132.
17.
KhouryMJBertramLBoffettaP, et al.Genome-wide association studies, field synopses, and the development of the knowledge base on genetic variation and human diseases. Am J Epidemiol2009; 170: 269–279.
18.
WacholderSChanockSGarcia-ClosasM, et al.Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst2004; 96: 434–442.
19.
WardLDKellisM. Haploreg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res2012; 40: D930–D934.
20.
McKinseyTA. Targeting inflammation in heart failure with histone deacetylase inhibitors. Mol Med2011; 17: 434–441.
21.
GrbicEGorkicNPleskovicA, et al.Association between rs2107595 HDAC9 gene polymorphism and advanced carotid atherosclerosis in the Slovenian cohort. Lipids Health Dis2020; 19: 71.
22.
BrookesRLCrichtonSWolfeCDA, et al.Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke2018; 49: 54–61.
23.
PalmFAignerAPussinenPJ, et al.Association of a multigenetic pro-inflammatory profile with ischaemic stroke. Cerebrovasc Dis2020; 49: 170–176.
24.
ShroffNAnderBPZhanX, et al.HDAC9 polymorphism alters blood gene expression in patients with large vessel atherosclerotic stroke. Transl Stroke Res2019; 10: 19–25.
25.
LansdellTAFisherCSimmondsK, et al.Rs10230207 genotype confers changes in HDAC9 and TWIST1, but not FERD3L in lymphoblasts from patients with intracranial aneurysm. Neurogenetics2019; 20: 83–89.
26.
QingxuGYanZJiannanX, et al.Association between the gene polymorphisms of HDAC9 and the risk of atherosclerosis and ischemic stroke. Pathol Oncol Res2016; 22: 103–107.
27.
FerronatoSGelatiMScuroA, et al.HDAC9, TWIST1 and FERD3L gene expression in asymptomatic stable and unstable carotid plaques. Inflamm Res2016; 65: 261–263.
28.
MarkusHS. HDAC9 Inhibition as a novel treatment for stroke. Stroke2023; 54: 3182–3189.
29.
HaberlandMArnoldMAMcAnallyJ, et al.Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation. Mol Cell Biol2007; 27: 518–525.
30.
LecceLXuYV'GangulaB, et al.Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype. J Clin Invest2021; 131: e131178.
