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Rs10230207 genotype confers changes in HDAC9 and TWIST1, but not FERD3L in lymphoblasts from patients with intracranial aneurysm

  • Theresa A. LansdellEmail author
  • Courtney Fisher
  • Kent Simmonds
  • Mat J. Reeves
  • Daniel Woo
  • Anne M. Dorrance
  • Stacie L. Demel
Original Article
  • 53 Downloads

Abstract

Intracranial aneurysms (IA) are weakened outpouchings of the arterial wall in the cerebrovasculature. Rupture of an IA often leads to devastating consequences. The early identification of IA patients is crucial for management of their condition. A genetic variant at rs10230207, located nearby the HDAC9, TWIST1, and FERD3L genes, is associated with IA. HDAC9 is a class IIa histone deacetylase that mediates vascular smooth muscle cell dysfunction. TWIST1 is a mechanosensitive transcription factor and its expression is reduced in unstable carotid atherosclerotic plaques. In this study, the expression of the HDAC9, TWIST1, and FERD3L genes was characterized and associated with the presence of the rs10230207 genetic variant. Allelic discrimination and gene expression analysis were performed using lymphoblasts from 85 population controls and 109 IA patients. Subjects that were heterozygous (GT) within rs10230207 were 4.32 times more likely to have an IA than those that were homozygous for the reference allele (GG; 95%CI 1.23 to 14.16). Subjects that were homozygous (TT) were 8.27 times more likely to have an IA than those that were GG (95%CI 2.45 to 27.85). While the presence of the risk allele was not associated with changes in FERD3L gene expression, the risk allele was associated with increased HDAC9 and decrease in TWIST1 mRNA expression. The significant inverse correlation between HDAC9 and TWIST1 gene expression suggests that changes in the expression of both of genes may contribute to the formation of IAs.

Keywords

Intracranial aneurysm HDAC9 TWIST1 FERD3L rs10230207 

Notes

Acknowledgments

The authors would like to acknowledge Lauren Peruski for her work in generating subject information tables from the Coriell catalog.

Supplementary material

10048_2019_569_MOESM1_ESM.docx (43 kb)
ESM 1 (DOCX 42 kb)

References

  1. 1.
    Vlak MH, Algra A, Brandenburg R, Rinkel GJ (2011) Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 10:626–636CrossRefGoogle Scholar
  2. 2.
    Vernooij MW, Ikram MA, Tanghe HL, Vincent AJPE, Hofman A, Krestin GP, Niessen WJ, Breteler MMB, van der Lugt A (2007) Incidental findings on brain MRI in the general population. N Engl J Med 357:1821–1828CrossRefGoogle Scholar
  3. 3.
    Lantigua H, Ortega-Gutierrez S, Schmidt JM, Lee K, Badjatia N, Agarwal S, Claassen J, Connolly ES, Mayer SA (2015) Subarachnoid hemorrhage: who dies, and why? Crit Care 19:309CrossRefPubMedCentralGoogle Scholar
  4. 4.
    van Gijn J, Kerr RS, Rinkel GJE (2007) Subarachnoid haemorrhage. Lancet 369:306–318CrossRefGoogle Scholar
  5. 5.
    Jaja BNR, Lingsma H, Steyerberg EW, Schweizer TA, Thorpe KE, Macdonald RL, on behalf of SAHIT investigators (2016) Neuroimaging characteristics of ruptured aneurysm as predictors of outcome after aneurysmal subarachnoid hemorrhage: pooled analyses of the SAHIT cohort. J Neurosurg 124:1703–1711CrossRefGoogle Scholar
  6. 6.
    Leung HK, Lam Y, Cheng KM, Chan CM, Cheung YL (2011) Intracranial aneurysms in twins: case report and review of the literature. Hong Kong Med J 17:151–154Google Scholar
  7. 7.
    Belz MM, Fick-Brosnahan GM, Hughes RL, Rubinstein D, Chapman AB, Johnson AM, McFann KK, Kaehny WD, Gabow PA (2003) Recurrence of intracranial aneurysms in autosomal-dominant polycystic kidney disease. Kidney Int 63:1824–1830CrossRefGoogle Scholar
  8. 8.
    Mackey J, Brown RD, Sauerbeck L, Hornung R, Moomaw CJ, Koller DL, Foroud T, Deka R, Woo D, Kleindorfer D, Flaherty ML, Meissner I, Anderson C, Rouleau G, Connolly ES, Huston J, Broderick JP (2015) Affected twins in the familial intracranial aneurysm study. Cerebrovasc Dis 39:82–86CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Nakagawa T, Hashi K, Kurokawa Y, Yamamura A (1999) Family history of subarachnoid hemorrhage and the incidence of asymptomatic, unruptured cerebral aneurysms. J Neurosurg 91:391–395CrossRefGoogle Scholar
  10. 10.
    Ronkainen A, Hernesniemi J, Puranen M, Niemitukia L, Vanninen R, Ryynänen M, Kuivaniemi H, Tromp G (1997) Familial intracranial aneurysms. Lancet 349:380–384CrossRefGoogle Scholar
  11. 11.
    Hitchcock E, Gibson WT (2017) A review of the genetics of intracranial berry aneurysms and implications for genetic counseling. J Genet Couns 26:21–31CrossRefGoogle Scholar
  12. 12.
    Foroud T, Lai D, Koller D, Van’t Hof F, Kurki MI, Anderson CS, Brown RD, Connolly ES, Eriksson JG, Flaherty M, Fornage M, von Und Zu Fraunberg M, Gaál EI, Laakso A, Hernesniemi J, Huston J, Jääskeläinen JE, Kiemeney LA, Kivisaari R, Kleindorfer D, Ko N, Lehto H, Mackey J, Meissner I, Moomaw CJ, Mosley TH, Moskala M, Niemelä M, Palotie A, Pera J, Rinkel G, Ripke S, Rouleau G, Ruigrok Y, Sauerbeck L, Słowik A, Vermeulen SH, Woo D, Worrall BB, Broderick J (2014) Familial Intracranial Aneurysm Study Investigators. Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. Stroke 45:3194–3199CrossRefPubMedCentralGoogle Scholar
  13. 13.
    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 46:197–202CrossRefGoogle Scholar
  14. 14.
    NINDS Stroke Genetics Network (SiGN), International Stroke Genetics Consortium (ISGC) (2016) Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol 15:174–184CrossRefGoogle Scholar
  15. 15.
    Qingxu G, Yan Z, Jiannan X, Yunlong L (2016) Association between the gene polymorphisms of HDAC9 and the risk of atherosclerosis and ischemic stroke. Pathol Oncol Res 22:103–107CrossRefGoogle Scholar
  16. 16.
    Shroff N, Ander BP, Zhan X, Stamova B, Liu D, Hull H, Hamade FR, Dykstra-Aiello C, Ng K, Sharp FR, Jickling GC (2018) HDAC9 polymorphism alters blood gene expression in patients with large vessel atherosclerotic stroke. Transl Stroke ResGoogle Scholar
  17. 17.
    Wang X-B, Han Y, Sabina S, Cui N-H, Zhang S, Liu Z-J, Li C, Zheng F (2016) HDAC9 variant rs2107595 modifies susceptibility to coronary artery disease and the severity of coronary atherosclerosis in a chinese han population. PLoS One 11:e0160449CrossRefPubMedCentralGoogle Scholar
  18. 18.
    Hacke W, Grond-Ginsbach C (2012) Commentary on a GWAS: HDAC9 and the risk for ischaemic stroke. BMC Med 10:70CrossRefPubMedCentralGoogle Scholar
  19. 19.
    Lino Cardenas CL, Kessinger CW, Cheng Y, MacDonald C, MacGillivray T, Ghoshhajra B, Huleihel L, Nuri S, Yeri AS, Jaffer FA, Kaminski N, Ellinor P, Weintraub NL, Malhotra R, Isselbacher EM, Lindsay ME (2018) An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nat Commun 9:1009CrossRefPubMedCentralGoogle Scholar
  20. 20.
    Galán M, Varona S, Orriols M, Rodríguez JA, Aguiló S, Dilmé J, Camacho M, Martínez-González J, Rodriguez C (2016) Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors. Dis Model Mech 9:541–552CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Vinh A, Gaspari TA, Liu HB, Dousha LF, Widdop RE, Dear AE (2008) A novel histone deacetylase inhibitor reduces abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice. J Vasc Res 45:143–152CrossRefGoogle Scholar
  22. 22.
    Mahmoud MM, Kim HR, Xing R, Hsiao S, Mammoto A, Chen J, Serbanovic-Canic J, Feng S, Bowden NP, Maguire R, Ariaans M, Francis SE, Weinberg PD, van der Heiden K, Jones EA, Chico TJA, Ridger V, Evans PC (2016) TWIST1 integrates endothelial responses to flow in vascular dysfunction and atherosclerosis. Circ Res 119:450–462CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Mahmoud MM, Serbanovic-Canic J, Feng S, Souilhol C, Xing R, Hsiao S, Mammoto A, Chen J, Ariaans M, Francis SE, Van der Heiden K, Ridger V, Evans PC (2017) Shear stress induces endothelial-to-mesenchymal transition via the transcription factor Snail. Sci Rep 7:3375CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Ferronato S, Gelati M, Scuro A, Olivato S, Malerba G, Romanelli MG, Gomez-Lira M, Setacci C (2016) HDAC9, TWIST1 and FERD3L gene expression in asymptomatic stable and unstable carotid plaques. Inflamm Res 65:261–263CrossRefGoogle Scholar
  25. 25.
    Zhang JD, Ruschhaupt M, Biczok R. ddCt method for qRT–PCR data analysisGoogle Scholar
  26. 26.
    Sasaki T, Kakizawa Y, Yoshino M, Fujii Y, Yoroi I, Ichikawa Y, Horiuchi T, Hongo K (2018) Numerical analysis of bifurcation angles and branch patterns in intracranial aneurysm formation. NeurosurgeryGoogle Scholar
  27. 27.
    DeBusk LM, Hallahan DE, Lin PC (2004) Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway. Exp Cell Res 298:167–177CrossRefGoogle Scholar
  28. 28.
    Mammoto T, Jiang E, Jiang A, Lu Y, Juan AM, Chen J, Mammoto A (2013) Twist1 controls lung vascular permeability and endotoxin-induced pulmonary edema by altering Tie2 expression. PLoS One 8:e73407CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Behera V, Evans P, Face CJ, Hamagami N, Sankaranarayanan L, Keller CA, Giardine B, Tan K, Hardison RC, Shi J, Blobel GA (2018) Exploiting genetic variation to uncover rules of transcription factor binding and chromatin accessibility. Nat Commun 9:782CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, Thurman RE, Kaul R, Myers RM, Stamatoyannopoulos JA (2012) Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res 22:1680–1688CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyMichigan State UniversityEast LansingUSA
  2. 2.Department of Epidemiology and BiostatisticsMichigan State UniversityEast LansingUSA
  3. 3.Department of NeurologyUniversity of Cincinnati College of MedicineCincinnatiUSA
  4. 4.Department of Neurology and OphthalmologyMichigan State UniversityEast LansingUSA

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