Background and Aim Previous studies indicated that the HDAC3 and HDAC9 genes play critical roles in atherosclerosis and ischemic stroke (IS). The purpose of this study was to investigate the association of combined single-nucleotide polymorphisms in the HDAC3 and HDAC9 genes with the susceptibility to IS. Methods A case-control study was conducted including 863 IS patients and 863 age- and gender-matched healthy participants. A polygenic score was developed to estimate the contribution of a combination of the HDAC3 and HDAC9 genes to the risk of IS. The interactive effects of traditional risk factors of stroke and the polygenic score on the risk of IS were explored. Additionally, the association between the polygenic score and the progression of atherosclerosis, a potential risk factor of IS, was examined in our healthy controls. Results Subjects with a higher polygenic score had an increased risk of IS (odds ratio: 1.83; 95% confidence interval: 1.38-2.43) after adjusting for covariates compared with individuals with a lower polygenic score. An interactive effect of diabetes mellitus and the polygenic score on the risk of IS was observed. A significant positive correlation between the polygenic score and a change in the plaque score (standardized β = 0.42, p = 0.0235) in healthy controls with diabetes mellitus was found. Conclusion Our results suggested that the combination of the HDAC3 and HDAC9 genes with a history of diabetes mellitus could exacerbate the deterioration of atherosclerosis, thereby increasing the risk of IS. Further studies are warranted to explore our results in other populations.
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