Abstract
Recently, a genome-wide association study (GWAS) detected two histone deacetylase 9 (HDAC9) polymorphisms (rs2074633 and rs28688791) which may be associated with risk of large artery atherosclerotic (LAA) stroke. This study aimed to investigate whether these two polymorphisms were associated with susceptibility, severity, and short-term outcome of LAA stroke in a southern Chinese Han population. rs2074633 and rs28688791 were genotyped using SNPscan technology in 1011 LAA stroke patients and 1121 healthy controls. Stroke severity on admission and short-term outcome were, respectively, assessed by the National Institute of Health Stroke Scale (NIHSS) score on admission and modified Rankin Scale score at 3 months after stroke onset. rs2074633 (P = 0.039) and rs28688791 (P = 0.025) were associated with risk of LAA stroke. In subgroup analysis according to sex and age, this increased risk was only found in males (P = 0.029 for rs2074633; P = 0.013 for rs28688791) and adults aged < 60 years (P = 0.009 for rs2074633; P = 0.003 for rs28688791). Moreover, we detected significant interactions between these two polymorphisms and age (Pinteraction = 0.027 for rs2074633; Pinteraction = 0.044 for rs28688791). The CC genotype of rs28688791 (P = 0.037) was also associated with moderate and severe stroke (NIHSS ≥ 6). Additionally, the CC genotype of rs2074633 and rs28688791 (rs2074633, P = 0.019; rs28688791, P = 0.023) showed significant association with unfavorable short-term outcome of LAA stroke. Our results indicated that HDAC9 polymorphisms may be used as biomarkers for susceptibility, severity, and short-term outcome of LAA stroke.
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References
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41. https://doi.org/10.1161/01.STR.24.1.35
Ambrosius W, Michalak S, Kazmierski R, Lukasik M, Andrzejewska N, Kozubski W (2018) The association between serum matricellular protein: secreted protein acidic and rich in cysteine-like 1 levels and ischemic stroke severity. J Stroke Cerebrovasc Dis 27:682–685. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.060
Azghandi S, Prell C, van der Laan SW, Schneider M, Malik R, Berer K, Gerdes N, Pasterkamp G, Weber C, Haffner C, Dichgans M (2015) Deficiency of the stroke relevant HDAC9 gene attenuates atherosclerosis in accord with allele-specific effects at 7p21.1. Stroke 46:197–202. https://doi.org/10.1161/STROKEAHA.114.007213
Bevan S, Traylor M, Adib-Samii P, Malik R, Paul NLM, Jackson C, Farrall M, Rothwell PM, Sudlow C, Dichgans M, Markus HS (2012) Genetic heritability of ischemic stroke and the contribution of previously reported candidate gene and genomewide associations. Stroke 43:3161–3167. https://doi.org/10.1161/STROKEAHA.112.665760
Bouziana SD, Tziomalos K, Goulas A, Vyzantiadis TA, Panderi A, Etaatzitolios A (2018) Major adipokines and the -420C>G resistin gene polymorphism as predictors of acute ischemic stroke severity and in-hospital outcome. J Stroke Cerebrovasc Dis 27:963–970. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.10.038
Cao Q, Rong S, Repa JJ, St Clair R, Parks JS, Mishra N (2014) Histone deacetylase 9 represses cholesterol efflux and alternatively activated macrophages in atherosclerosis development. Arterioscler Thromb Vasc Biol 34:1871–1879. https://doi.org/10.1161/atvbaha.114.303393
Cheng YC et al (2016) Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 near HABP2. Stroke 47:307–316. https://doi.org/10.1161/strokeaha.115.011328
Dichgans M (2007) Genetics of ischaemic stroke. Lancet Neurol 6:149–161. https://doi.org/10.1016/s1474-4422(07)70028-5
Flossmann E, Schulz UG, Rothwell PM (2004) Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke 35:212–227. https://doi.org/10.1161/01.STR.0000107187.84390.AA
Han Y, Sun W, Wang L, Tao S, Tian L, Hao Y, Zhang W, Wu S, Li S, Lv H, Zheng SL, Sun J, Xu J (2013) HDAC9 gene is associated with stroke risk in a Chinese population. Exp Biol Med 238:842–847. https://doi.org/10.1177/1535370213494650
International Stroke Genetics C et al (2012) Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke. Nat Genet 44:328–333. https://doi.org/10.1038/ng.1081
Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gauguier D, Reid JL, Macrae IM, Dominiczak AF (1997) Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet 16:364–367. https://doi.org/10.1038/ng0897-364
Lee TH et al (2016) Identification of PTCSC3 as a novel locus for large-vessel ischemic stroke: a genome-wide association study. J Am Heart Assoc 5:e003003. https://doi.org/10.1161/JAHA.115.003003
Liu X, Xu G, Wu W, Zhang R, Yin Q, Zhu W (2006) Subtypes and one-year survival of first-ever stroke in Chinese patients: the Nanjing Stroke Registry. Cerebrovasc Dis 22:130–136. https://doi.org/10.1159/000093241
Lovkvist H, Jonsson AC, Luthman H, Jood K, Jern C, Wieloch T, Lindgren A (2014) Variations in apolipoprotein D and sigma non-opioid intracellular receptor 1 genes with relation to risk, severity and outcome of ischemic stroke. BMC Neurol 14:191. https://doi.org/10.1186/s12883-014-0191-2
Maguire J et al (2011) Impact of COX-2 rs5275 and rs20417 and GPIIIa rs5918 polymorphisms on 90-day ischemic stroke functional outcome: a novel finding. J Stroke Cerebrovasc Dis 20:134–144. https://doi.org/10.1016/j.jstrokecerebrovasdis.2009.10.011
Markus HS, Mäkelä KM, Bevan S, Raitoharju E, Oksala N, Bis JC, O’Donnell C, Hainsworth A, Lehtimäki T (2013) Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. Stroke 44:1220–1225. https://doi.org/10.1161/STROKEAHA.111.000217
Minnerup J, Wersching H, Teuber A, Wellmann J, Eyding J, Weber R, Reimann G, Weber W, Krause LU, Kurth T, Berger K, for the REVASK Investigators, Homberg V, Petrovitch A, Heuser L, Mönnigs P, Krogias C, Wallner B, Hennigs S, Ahlers A, Sahl H, Ranft A, Dobis C, Brassel F, Nolden-Koch M, Schmitt H, Chapot R, Nordmeyer H, Schlamann M, Weimar C, Busch F, Busch EW, Sigges E, Ruf H, Wohlfahrt K, Karatschai R, Klein B, Höhle T, Haass A, Nasreldein A, Büchele B, Gahn G, Sterker M, Hantel T, Krämer C, Henningsen H, Adelt I, König M, Schmidt C, Hofmann A, Niederstadt T, Unrath M, Rehfeldt T, Fauser B, Pfeiffer A, Lowens S, Stögbauer F, Staudacher T, Erdmann P, Grotemeyer KH, Spüntrup E, Bücke P, Wienecke P, Faiss J, Wolzik-Großmann M, Brune N, Isenmann S, Thomas C, Mucha D (2016) Outcome after thrombectomy and intravenous thrombolysis in patients with acute ischemic stroke: a prospective observational study. Stroke 47:1584–1592. https://doi.org/10.1161/STROKEAHA.116.012619
Ovbiagele B, Saver JL (2010) Day-90 acute ischemic stroke outcomes can be derived from early functional activity level. Cerebrovasc Dis 29:50–56. https://doi.org/10.1159/000255974
Schulz UG, Flossmann E, Rothwell PM (2004) Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke 35:819–824. https://doi.org/10.1161/01.STR.0000121646.23955.0f
Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929. https://doi.org/10.1093/bioinformatics/btl268
Touze E, Rothwell PM (2008) Sex differences in heritability of ischemic stroke: a systematic review and meta-analysis. Stroke 39:16–23. https://doi.org/10.1161/STROKEAHA.107.484618
Traylor M, Farrall M, Holliday EG, Sudlow C, Hopewell JC, Cheng YC, Fornage M, Ikram MA, Malik R, Bevan S, Thorsteinsdottir U, Nalls MA, Longstreth W, Wiggins KL, Yadav S, Parati EA, Destefano AL, Worrall BB, Kittner SJ, Khan MS, Reiner AP, Helgadottir A, Achterberg S, Fernandez-Cadenas I, Abboud S, Schmidt R, Walters M, Chen WM, Ringelstein EB, O’Donnell M, Ho WK, Pera J, Lemmens R, Norrving B, Higgins P, Benn M, Sale M, Kuhlenbäumer G, Doney AS, Vicente AM, Delavaran H, Algra A, Davies G, Oliveira SA, Palmer CN, Deary I, Schmidt H, Pandolfo M, Montaner J, Carty C, de Bakker PI, Kostulas K, Ferro JM, van Zuydam N, Valdimarsson E, Nordestgaard BG, Lindgren A, Thijs V, Slowik A, Saleheen D, Paré G, Berger K, Thorleifsson G, Australian Stroke Genetics Collaborative, Wellcome Trust Case Control Consortium 2 (WTCCC2), Hofman A, Mosley TH, Mitchell BD, Furie K, Clarke R, Levi C, Seshadri S, Gschwendtner A, Boncoraglio GB, Sharma P, Bis JC, Gretarsdottir S, Psaty BM, Rothwell PM, Rosand J, Meschia JF, Stefansson K, Dichgans M, Markus HS, International Stroke Genetics Consortium (2012) Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 11:951–962. https://doi.org/10.1016/s1474-4422(12)70234-x
Wang L, Yanuck D, Beecham A, Gardener H, Slifer S, Blanton SH, Sacco RL, Rundek T (2011) A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque. Stroke 42:588–592. https://doi.org/10.1161/strokeaha.110.596841
Zhou X et al (2017) The association between HDAC9 gene polymorphisms and stroke risk in the Chinese population: a meta-analysis. Sci Rep 7:41538. https://doi.org/10.1038/srep41538
Funding
This study was supported by the National Natural Science Foundation of China (81771285, 81701184, 81530038, 81501019, and 81571148) and the China Postdoctoral Science Foundation (2016M592954).
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Wang, M., Gu, M., Li, Z. et al. HDAC9 Polymorphisms Predict Susceptibility, Severity, and Short-Term Outcome of Large Artery Atherosclerotic Stroke in Chinese Population. J Mol Neurosci 67, 165–171 (2019). https://doi.org/10.1007/s12031-018-1221-0
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DOI: https://doi.org/10.1007/s12031-018-1221-0