Skip to main content

Advertisement

SpringerLink
Log in

Common genetic polymorphisms in Moyamoya and atherosclerotic disease in Europeans

  • Original Paper
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Purpose

Moyamoya is the most common cerebrovascular disease in children in Japan. The disease's etiology is still widely unknown. Several publications describe histopathological changes in the walls of affected vessels similar to those seen in atherosclerosis. In this study, we analyzed the DNA of European patients with Moyamoya disease for single nucleotide polymorphisms associated with atherosclerotic changes.

Methods

We genotyped 17 SNPs in or adjacent to 11 genes (ELN, LIMK1, CDKN2A/B, CXCL12, Pseudogene ENSG00000197218, PSRC1, MTHFD1L, SMAD3, MIA3, PDGF-B, TIMP2) comparing 40 DNA samples of Moyamoya disease patients to 68 healthy controls from central Europe. The mean age of onset of Moyamoya disease (MMD)-related symptoms was 15.4 years of age. Genotyping was performed by sequencing the SNP containing genetic regions with custom-made primers.

Results

We found strong association of one SNP (rs599839 [A/G], OR = 2.17, 95% CI = 1.17, 4.05; p = 0.01) with the risk allele G located in the 3′ UTR region of the PSRC-1 gene. Three further SNPs (rs8326, rs34208922, rs501120) in or adjacent to the genes ELN and CXCL12 showed tendencies towards risk alleles with p values between 0.1 and 0.2 but did not reach statistical significance in our cohort.

Conclusions

Our results indicate a possible parallel of common processes in the genesis of Moyamoya disease and atherosclerotic disease. Further analyses in larger European cohorts and replication in patients of different ethnicity may lead to possible early detection of patients at risk for developing MMD and subsequently to future causative therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Achrol AS, Guzman R, Lee M, Steinberg GK (2009) Pathophysiology and genetic factors in Moyamoya disease. Neurosurg Focus 26:E4

    Article  PubMed  Google Scholar 

  2. Scott RM, Smith ER (2009) Moyamoya disease and Moyamoya syndrome. N Engl J Med 360:1226–1237

    Article  CAS  PubMed  Google Scholar 

  3. Takeuchi K, Shimizu K (1957) Hypoplasia of the bilateral internal carotid arteries. Brain Nerve 9:37–43

    Google Scholar 

  4. Suzuki J, Takaku A (1969) Cerebrovascular “Moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20:288–299

    CAS  PubMed  Google Scholar 

  5. Aoyagi M, Fukai N, Yamamoto M, Nakagawa K, Matsushima Y, Yamamoto K (1996) Early development of intimal thickening in superficial temporal arteries in patients with Moyamoya disease. Stroke 27:1750–1754

    CAS  PubMed  Google Scholar 

  6. Takebayashi S, Matsuo K, Kaneko M (1984) Ultrastructural studies of cerebral arteries and collateral vessels in Moyamoya disease. Stroke 15:728–732

    CAS  PubMed  Google Scholar 

  7. Ikeda E (1991) Systemic vascular changes in spontaneous occlusion of the circle of Willis. Stroke 22:1358–1362

    CAS  PubMed  Google Scholar 

  8. Li B, Wang CC, Zhao ZZ, Hu Y, Aihara K, Ghazizadeh M, Sasaki Y, Yang SY, Pan J (1991) A histological, ultrastructural and immunohistochemical study of superficial temporal arteries and middle meningeal arteries in Moyamoya disease. Acta Pathol Jpn 41:521–530

    CAS  PubMed  Google Scholar 

  9. Takagi Y, Kikuta K, Nozaki K, Fujimoto M, Hayashi J, Imamura H, Hashimoto N (2007) Expression of hypoxia-inducing factor-1 alpha and endoglin in intimal hyperplasia of the middle cerebral artery of patients with Moyamoya disease. Neurosurgery 60:338

    Article  PubMed  Google Scholar 

  10. Masuda J, Ogata J, Yutani C (1993) Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in Moyamoya disease. Stroke 24:1960–1967

    CAS  PubMed  Google Scholar 

  11. Yamamoto M, Aoyagi M, Fukai N, Matsushima Y, Yamamoto K (1998) Differences in cellular responses to mitogens in arterial smooth muscle cells derived from patients with Moyamoya disease. Stroke 29:1188–1193

    CAS  PubMed  Google Scholar 

  12. Kang HS, Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC (2006) Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial Moyamoya disease. Neurosurgery 58:1074–1080

    Article  PubMed  Google Scholar 

  13. Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, Onda H, Hori T, Kubota M, Machida T, Saeki N, Hata A, Hashiguchi K, Kimura E, Kim CJ, Yang TK, Lee JY, Kimm K, Inoue I (2006) A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Hum Mol Genet 15:1722–1734

    Article  CAS  PubMed  Google Scholar 

  14. Tambur AR, Pamboukian S, Costanzo MR, Heroux A (2006) Genetic polymorphism in platelet-derived growth factor and vascular endothelial growth factor are significantly associated with cardiac allograft vasculopathy. J Heart Lung Transplant 25:690–698

    Article  PubMed  Google Scholar 

  15. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA, Pennacchio LA, Tybjaerg-Hansen A, Folsom AR (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316:1488–1491

    Article  CAS  PubMed  Google Scholar 

  16. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, Jonasdottir A, Sigurdsson A, Baker A, Palsson A, Masson G, Gudbjartsson DF, Magnusson KP, Andersen K, Levey AI, Backman VM, Matthiasdottir S, Jonsdottir T, Palsson S, Einarsdottir H, Gunnarsdottir S, Gylfason A, Vaccarino V, Hooper WC, Reilly MP, Granger CB, Austin H, Rader DJ, Shah SH, Quyyumi AA, Gulcher JR, Thorgeirsson G, Thorsteinsdottir U, Kong A, Stefansson K (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316:1491–1493

    Article  CAS  PubMed  Google Scholar 

  17. Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann HE, Barrett JH, Konig IR, Stevens SE, Szymczak S, Tregouet D-A, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F, Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG, Strom TM, Braenne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson JR, Schunkert H, WTCCC and the Cardiogenics Consortium (2007) Genomewide association analysis of coronary artery disease. N Engl J Med 357:443–453

    Article  CAS  PubMed  Google Scholar 

  18. Mineharu Y, Liu W, Inoue K, Matsuura N, Inoue S, Takenaka K, Ikeda H, Houkin K, Takagi Y, Kikuta K, Nozaki K, Hashimoto N, Koizumi A (2008) Autosomal dominant Moyamoya disease maps to chromosome 17q25.3. Neurology 70:2357–2363

    Article  CAS  PubMed  Google Scholar 

  19. Vairaktaris E, Yapijakis C, Yiannopoulos A, Vassiliou S, Serefoglou Z, Vylliotis A, Nkenke E, Derka S, Critselis E, Avgoustidis D (2007) Strong association of the tissue inhibitor of metalloproteinase-2 polymorphism with an increased risk of oral squamous cell carcinoma in Europeans. Oncol Rep 17:963

    CAS  PubMed  Google Scholar 

  20. Karnik SK, Brooke BS, Bayes-Genis A, Sorensen L, Wythe JD, Schwartz RS, Keating MT, Li DY (2003) A critical role for elastin signaling in vascular morphogenesis and disease. Development 130:411–423

    Article  CAS  PubMed  Google Scholar 

  21. Sandhu MS, Waterworth DM, Debenham SL, Wheeler E, Papadakis K, Zhao JH, Song K, Yuan X, Johnson T, Ashford S (2008) LDL-cholesterol concentrations: a genome-wide association study. Lancet 371:483–491

    Article  CAS  PubMed  Google Scholar 

  22. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, Heath SC, Timpson NJ, Najjar SS, Stringham HM (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40:161–169

    Article  CAS  PubMed  Google Scholar 

  23. Samani NJ, Braund PS, Erdmann J, Götz A, Tomaszewski M, Linsel-Nitschke P, Hajat C, Mangino M, Hengstenberg C, Stark K (2008) The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol. J Mol Med 86:1233–1241

    Article  CAS  PubMed  Google Scholar 

  24. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, Cooper GM, Roos C, Voight BF, Havulinna AS (2008) Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40:189–197

    Article  CAS  PubMed  Google Scholar 

  25. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  26. Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C (2008) Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6:e107

    Article  PubMed  Google Scholar 

  27. Consortium CAD (2009) Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler Thromb Vasc Biol 29:774–780

    Article  Google Scholar 

  28. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, Rovner A, Ellis SG, Thomas JD, DiCorleto PE (2003) Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362:697–703

    Article  CAS  PubMed  Google Scholar 

  29. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864

    Article  CAS  PubMed  Google Scholar 

  30. Zheng H, Fu G, Dai T, Huang H (2007) Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1 [alpha]/CXCR4 via PI3K/Akt/eNOS signal transduction pathway. J Cardiovasc Pharmacol 50:274

    Article  CAS  PubMed  Google Scholar 

  31. Horuk R (2001) Chemokine receptors. Cytokine Growth Factor Rev 12:313–335

    Article  CAS  PubMed  Google Scholar 

  32. Mirshahi F, Pourtau J, Li H, Muraine M, Trochon V, Legrand E, Vannier JP, Soria J, Vasse M, Soria C (2000) SDF-1 activity on microvascular endothelial cells consequences on angiogenesis in in vitro and in vivo models. Thromb Res 99:587–594

    Article  CAS  PubMed  Google Scholar 

  33. Weis M, von Scheidt W (1997) Cardiac allograft vasculopathy: a review. Circulation 96:2069–2077

    CAS  PubMed  Google Scholar 

  34. Aoyagi M, Fukai N, Matsushima Y, Yamamoto M, Yamamoto K (1993) Kinetics of 125I-PDGF binding and down-regulation of PDGF receptor in arterial smooth muscle cells derived from patients with Moyamoya disease. J Cell Physiol 154:281–288

    Article  CAS  PubMed  Google Scholar 

  35. Aoyagi M, Fukai N, Sakamoto H, Shinkai T, Matsushima Y, Yamamoto M, Yamamoto K (1991) Altered cellular responses to serum mitogens, including platelet-derived growth factor, in cultured smooth muscle cells derived from arteries of patients with Moyamoya disease. J Cell Physiol 147:191–198

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was partly supported by a grant-in-aid for scientific research (C) from the grant Encouraging Development of Strategic Research Centers and Special Coordination Funds for Promoting Science and Technology both from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Conflicts of interest/disclosures

None.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany

    Constantin Roder, Vera Peters, Marcos Tatagiba & Boris Krischek

  2. Division of Neurosurgery, Medical Center East, Tokyo Women’s Medical University, 2-1-10 Nishiogu, Arakawa-ku, Tokyo, 116-8567, Japan

    Hidetoshi Kasuya

  3. Tokyo Women’s Medical University and International Research and Educational Institute for Integrated Medical Sciences, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Tsutomu Nishizawa & Yayoi Takehara

  4. Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases (DZNE), Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany

    Daniela Berg

  5. The Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany

    Claudia Schulte

  6. Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, 300 Pasteur Drive, Boswell Building, A301, Stanford, CA, 94305-5327, USA

    Nadia Khan

Authors
  1. Constantin Roder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vera Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hidetoshi Kasuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsutomu Nishizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yayoi Takehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniela Berg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Claudia Schulte
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nadia Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marcos Tatagiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Boris Krischek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Boris Krischek.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roder, C., Peters, V., Kasuya, H. et al. Common genetic polymorphisms in Moyamoya and atherosclerotic disease in Europeans. Childs Nerv Syst 27, 245–252 (2011). https://doi.org/10.1007/s00381-010-1241-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-010-1241-8

Keywords

Search

Navigation