Translational Stroke Research

, Volume 4, Issue 3, pp 375–378

Polymorphisms in ACVRL1 and Endoglin Genes are Not Associated with Sporadic and HHT-Related Brain AVMs in Dutch Patients

  • Kim Boshuisen
  • Manon Brundel
  • Carolien G. F. de Kovel
  • Tom G. Letteboer
  • Gabriel J. E. Rinkel
  • Cornelis J. J. Westermann
  • Helen Kim
  • Ludmila Pawlikowska
  • Bobby P. C. Koeleman
  • Catharina J. M. Klijn
BRIEF COMMUNICATIONS

Abstract

We aimed to replicate the association of the IVS3-35A>G polymorphism in the activin receptor-like kinase (ACVRL) 1 gene and the 207G>A polymorphism in the endoglin (ENG) gene with sporadic brain arteriovenous malformations (BAVM) in Dutch BAVM patients. In addition, we assessed whether these polymorphisms contribute to the risk of BAVM in patients with hereditary haemorrhagic telangiectasia type 1 (HHT1). We genotyped 143 Dutch sporadic BAVM patients and 360 healthy volunteers for four variants in the ACVRL1 gene including IVS3-35A>G and two variants in the ENG gene including 207G>A. Differences in allele and genotype frequencies between sporadic BAVM patients and controls and their combined effect were analysed with a likelihood ratio test. Furthermore, we compared the allele and genotype frequencies between 24 HHT1 patients with a BAVM with those of a relative with HHT1 without a BAVM in a matched pair analysis using Wilcoxon signed rank test. No significant differences in allele frequency were found between sporadic BAVM cases and controls or between HHT1 patients with and without BAVM for any of the polymorphisms or the combination of ACVRL1 and ENG polymorphisms. Meta-analysis of the current and the two previous studies for the ACVRL1 IVS3-35A polymorphism showed a persisting association between the ACVRL1 IVS3-35A polymorphism and risk of sporadic BAVM (odds ratio, 1.86; 95 % CI: 1.32–2.61, p < 0.001). We did not replicate the previously found association between a polymorphism in ACVRL1 IVS3-35A>G and BAVM in Dutch patients. However, meta-analysis did not rule out a possible effect.

Keywords

Arteriovenous malformations Aetiology Genetics Neurogenetics Cerebrovascular disease 

References

  1. 1.
    Young WL, Yang GY. Are there genetic influences on sporadic brain arteriovenous malformations? Stroke. 2004;35:2740–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Kim H, Su H, Weinsheimer S, Pawlikowska L, Young WL. Brain arteriovenous malformation pathogenesis: a response-to-injury paradigm. Acta Neurochir Suppl. 2011;111:83–92.PubMedCrossRefGoogle Scholar
  3. 3.
    Weinsheimer SM, Xu H, Achrol AS, Stamova B, McCulloch CE, Pawlikowska L, Tian Y, Ko NU, Lawton MT, Steinberg GK, Chang SD, Jickling G, Ander BP, Kim H, Sharp FR, Young WL. Gene expression profiling of blood in brain arteriovenous malformation patients. Trans Stroke Res. 2011;2:575–87.CrossRefGoogle Scholar
  4. 4.
    van Beijnum J, Van der Worp HB, Schippers HM, van Nieuwenhuizen O, Kappelle LJ, Rinkel GJ, Berkelbach van der Sprenkel JW, Klijn CJ. Familial occurrence of brain arteriovenous malformations: a systematic review. J Neurol Neurosurg Psychiatry. 2007;78:1213–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Letteboer TG, Mager JJ, Snijder RJ, Koeleman BP, Lindhout D, Ploos van Amstel JK, Westermann CJ. Genotype–phenotype relationship in hereditary haemorrhagic telangiectasia. J Med Genet. 2006;43:371–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Sabba C, Pasculli G, Lenato GM, Suppressa P, Lastella P, Memeo M, Dicuonzo F, Guant G. Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers. J Thromb Haemost. 2007;5:1149–57.PubMedCrossRefGoogle Scholar
  7. 7.
    Bayrak-Toydemir P, McDonald J, Markewitz B, Lewin S, Miller F, Chou LS, Gedge F, Tang W, Coon H, Mao R. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Am J Med Genet A. 2006;140:463–70.PubMedGoogle Scholar
  8. 8.
    Lesca G, Olivieri C, Burnichon N, Pagella F, Carette MF, Gilbert-Dussardier B, Goizet C, Roume J, Rabilloud M, Saurin JC, Cottin V, Honnorat J, Coulet F, Giraud S, Calender A, Danesino C, Buscarini E, Plauchu H, French–Italian-Rendu-Osler Network. Genotype–phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French–Italian HHT network. Genet Med. 2007;9:14–22.PubMedCrossRefGoogle Scholar
  9. 9.
    Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet. 2006;43:97–110.PubMedCrossRefGoogle Scholar
  10. 10.
    Pawlikowska L, Tran MN, Achrol AS, Ha C, Burchard E, Choudhry S, Zaroff J, Lawton MT, Castro R, McCulloch CE, Marchuk D, Kwok PY, Young WL, UCSF BAVM Study Project. Polymorphisms in transforming growth factor-beta-related genes ALK1 and ENG are associated with sporadic brain arteriovenous malformations. Stroke. 2005;36:2278–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Simon M, Franke D, Ludwig M, Aliashkevich AF, Koster G, Oldenburg J, Bostrom A, Ziegler A, Schram J. Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. J Neurosurg. 2006;104:945–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol. 2003;25:115–21.PubMedCrossRefGoogle Scholar
  13. 13.
    Ioannidis JP. Why most discovered true associations are inflated. Epidemiology. 2008;19:640–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Kim Boshuisen
    • 1
  • Manon Brundel
    • 1
  • Carolien G. F. de Kovel
    • 2
  • Tom G. Letteboer
    • 2
  • Gabriel J. E. Rinkel
    • 1
  • Cornelis J. J. Westermann
    • 3
  • Helen Kim
    • 4
  • Ludmila Pawlikowska
    • 4
  • Bobby P. C. Koeleman
    • 2
  • Catharina J. M. Klijn
    • 1
  1. 1.Department of Neurology and Neurosurgery, Rudolf Magnus Institute of NeurosciencesUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of Biomedical Genetics and Complex GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
  3. 3.Department of PulmonologySt. Antonius HospitalNieuwegeinThe Netherlands
  4. 4.Departments of Anesthesia, Epidemiology and BiostatisticsUniversity of California–San FranciscoSan FranciscoUSA

Personalised recommendations