Skip to main content

Advertisement

SpringerLink
Log in

Analysis of human leucocyte antigen genes in Caucasian patients with idiopathic Moyamoya angiopathy

  • Experimental research
  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Abstract

Background

The etiology and genetic susceptibility of Moyamoya angiopathy (MMA) (Moyamoya disease, Moyamoya syndrome and unilateral type of MMA) still remain unclear. In Asian patient cohorts several HLA markers were described to be associated with MMA, but in Caucasians very little is known about genetic susceptibility of this angiopathy.

Method

We analysed DNA of 33 Caucasian patients with MMA for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 markers, respectively. HLA frequencies of all 33 patients with MMA were compared with HLA-frequencies of Caucasian controls. Additionally, subgroup analysis of 22 patients with Moyamoya disease (MMD) and 11 patients with unilateral type of MMA was performed.

Findings

Significant association was observed for HLA-DRB1*03 and HLA-DRB1*13 in all 33 patients (P c < 0.001 and P c < 0.001, respectively). Moreover, HLA-A*02 (P c = 0.009); HLA-B*08 (P c = 0.009), and HLA-DQB1*03 (P c = 0.003) frequencies were higher in all patients with MMA when compared with the controls. In addition, in 22 patients with MMD a higher frequency of HLA-DRB1*03 (P c < 0.001) was observed when compared with controls.

Conclusions

The results of this study indicate a putative association of HLA markers with MMA in Caucasian patients. Further studies are needed to elucidate the role of human MHC in the pathogenesis of this angiopathy.

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

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. Andreone V, Ciarmiello A, Fusco C, Ambrosanio G, Florio C, Linfante I (1999) Moyamoya disease in Italian monozygotic twins. Neurology 53:1332–1335

    PubMed  CAS  Google Scholar 

  3. Aoyagi M, Ogami K, Matsushima Y, Shikata M, Yamamoto M, Yamamoto K (1995) Human leukocyte antigen in patients with moyamoya disease. Stroke 26:415–417

    Article  PubMed  CAS  Google Scholar 

  4. Bax M, van Heemst J, Huizinga TW, Toes RE (2011) Genetics of rheumatoid arthritis: what have we learned? Immunogenetics 63:459–466

    Article  PubMed  CAS  Google Scholar 

  5. Chessman D, Kostenko L, Lethborg T, Purcell AW, Williamson NA, Chen Z, Kjer-Nielsen L, Mifsud NA, Tait BD, Holdsworth R, Almeida CA, Nolan D, Macdonald WA, Archbold JK, Kellerher AD, Marriott D, Mallal S, Bharadwaj M, Rossjohn J, McCluskey J (2008) Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28:822–832

    Article  PubMed  CAS  Google Scholar 

  6. Fukui M (1997) Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 99(Suppl 2):S238–S240

    PubMed  Google Scholar 

  7. Goyal MS, Hallemeier CL, Zipfel GJ, Rich KM, Grubb RL Jr, Chicoine MR, Moran CJ, Cross DT 3rd, Dacey RG Jr, Derdeyn CP (2010) Clinical features and outcome in North American adults with idiopathic basal arterial occlusive disease without moyamoya collaterals. Neurosurgery 67:278–285

    Article  PubMed  Google Scholar 

  8. Guo DC, Papke CL, Tran-Fadulu V, Regalado ES, Avidan N, Johnson RJ, Kim DH, Pannu H, Willing MC, Sparks E, Pyeritz RE, Singh MN, Dalman RL, Grotta JC, Marian AJ, Boerwinkle EA, Frazier LQ, LeMaire SA, Coselli JS, Estrera AL, Safi HJ, Veeraraghavan S, Muzny DM, Wheeler DA, Willerson JT, Yu RK, Shete SS, Scherer SE, Raman CS, Buja LM, Milewicz DM (2009) Mutations in smooth muscle alpha-actin (ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet 84:617–627

    Article  PubMed  CAS  Google Scholar 

  9. Han H, Pyo CW, Yoo DS, Huh PW, Cho KS, Kim DS (2003) Associations of Moyamoya patients with HLA class I and class II alleles in the Korean population. J Korean Med Sci 18:876–880

    PubMed  Google Scholar 

  10. Heinemann FM (2009) HLA genotyping and antibody characterization using the Luminex multiplex technology. Transfus Med Hemother 36:273–278

    Article  PubMed  Google Scholar 

  11. Herve D, Touraine P, Verloes A, Miskinyte S, Krivosic V, Logeart D, Alili N, Laredo JD, Gaudric A, Houdart E, Metzger JP, Tournier-Lasserve E, Woimant F (2010) A hereditary moyamoya syndrome with multisystemic manifestations. Neurology 75:259–264

    Article  PubMed  CAS  Google Scholar 

  12. Hong SH, Wang KC, Kim SK, Cho BK, Park MH (2009) Association of HLA-DR and -DQ genes with familial Moyamoya disease in Koreans. J Korean Neurosurg Soc 46:558–563

    Article  PubMed  CAS  Google Scholar 

  13. Houkin K, Abe H, Yoshimoto T, Takahashi A (1996) Is "unilateral" moyamoya disease different from moyamoya disease? J Neurosurg 85:772–776

    Article  PubMed  CAS  Google Scholar 

  14. Ikeda H, Sasaki T, Yoshimoto T, Fukui M, Arinami T (1999) Mapping of a familial moyamoya disease gene to chromosome 3p24.2-p26. Am J Hum Genet 64:533–537

    Article  PubMed  CAS  Google Scholar 

  15. Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M (2000) Linkage analysis of moyamoya disease on chromosome 6. J Child Neurol 15:179–182

    Article  PubMed  CAS  Google Scholar 

  16. Inoue TK, Ikezaki K, Sasazuki T, Ono T, Kamikawaji N, Matsushima T, Fukui M (1997) DNA typing of HLA in the patients with moyamoya disease. Jpn J Hum Genet 42:507–515

    Article  PubMed  CAS  Google Scholar 

  17. Kamada F, Aoki Y, Narisawa A, Abe Y, Komatsuzaki S, Kikuchi A, Kanno J, Niihori T, Ono M, Ishii N, Owada Y, Fujimura M, Mashimo Y, Suzuki Y, Hata A, Tsuchiya S, Tominaga T, Matsubara Y, Kure S (2011) A genome-wide association study identifies RNF213 as the first Moyamoya disease gene. J Hum Genet 56:34–40

    Article  PubMed  CAS  Google Scholar 

  18. Khan N, Schuknecht B, Boltshauser E, Capone A, Buck A, Imhof HG, Yonekawa Y (2003) Moyamoya disease and Moyamoya syndrome: experience in Europe; choice of revascularisation procedures. Acta Neurochir (Wien) 145:1061–1071, discussion 1071

    Article  CAS  Google Scholar 

  19. Kim SJ, Heo KG, Shin HY, Bang OY, Kim GM, Chung CS, Kim KH, Jeon P, Kim JS, Hong SC, Lee KH (2010) Association of thyroid autoantibodies with moyamoya-type cerebrovascular disease: a prospective study. Stroke 41:173–176

    Article  PubMed  Google Scholar 

  20. Kitahara T, Okumura K, Semba A, Yamaura A, Makino H (1982) Genetic and immunologic analysis on moya-moya. J Neurol Neurosurg Psychiatry 45:1048–1052

    Article  PubMed  CAS  Google Scholar 

  21. Kraemer M, Berlit P (2010) Primary central nervous system vasculitis and moyamoya disease: similarities and differences. J Neurol 257:816–819

    Article  PubMed  Google Scholar 

  22. Kraemer M, Berlit P, Diesner F, Khan N (2011) What is the expert’s option on antiplatelet therapy in moyamoya disease? Results of a worldwide Survey. Eur J Neurol. doi:10.1111/j.1468-1331.2011.03481.x

  23. Kraemer M, Heienbrok W, Berlit P (2008) Moyamoya disease in Europeans. Stroke 39:3193–3200

    Article  PubMed  Google Scholar 

  24. Kraemer MHF, Horn P, Venker C, Berlit P, Krischek B, Khan N (2011) Inheritance of Moyamoya disease in a Caucasian familiy. Eur J Neurol. doi:10.1111/j.1468-1331.2011.03536.x

  25. Kramer M, Berlit P (2010) [Moyamoya disease - a rare vasculopathy in Europeans]. Fortschr Neurol Psychiatr 78:542–550, quiz 551

    Article  PubMed  CAS  Google Scholar 

  26. Krischek B, Kasuya H, Khan N, Tatagiba M, Roder C, Kraemer M (2011) Genetic and clinical characteristics of Moyamoya disease in Europeans. Acta neurochirurgica Supplement 112

  27. Li H, Zhang ZS, Dong ZN, Ma MJ, Yang WZ, Han C, Du MM, Liu YX, Yang H, Liu W, Duan L, Cao WC (2011) Increased thyroid function and elevated thyroid autoantibodies in pediatric patients with moyamoya disease: a case–control study. Stroke 42:1138–1139

    Article  PubMed  CAS  Google Scholar 

  28. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta K, Takagi Y, Harada KH, Fujiyama A, Herzig R, Krischek B, Zou L, Kim JE, Kitakaze M, Miyamoto S, Nagata K, Hashimoto N, Koizumi A (2011) Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 6:e22542

    Article  PubMed  CAS  Google Scholar 

  29. Maiers M, Gragert L, Klitz W (2007) High-resolution HLA alleles and haplotypes in the United States population. Hum Immunol 68:779–788

    Article  PubMed  CAS  Google Scholar 

  30. Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359:727–732

    Article  PubMed  CAS  Google Scholar 

  31. Martorana D, Vaglio A, Greco P, Zanetti A, Moroni G, Salvarani C, Savi M, Buzio C, Neri TM (2006) Chronic periaortitis and HLA-DRB1*03: another clue to an autoimmune origin. Arthritis Rheum 55:126–130

    Article  PubMed  CAS  Google Scholar 

  32. Milewicz DM, Ostergaard JR, Ala-Kokko LM, Khan N, Grange DK, Mendoza-Londono R, Bradley TJ, Olney AH, Ades L, Maher JF, Guo D, Buja LM, Kim D, Hyland JC, Regalado ES (2010) De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A 152A:2437–2443

    Article  PubMed  Google Scholar 

  33. 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  PubMed  CAS  Google Scholar 

  34. Mineharu Y, Takenaka K, Yamakawa H, Inoue K, Ikeda H, Kikuta KI, Takagi Y, Nozaki K, Hashimoto N, Koizumi A (2006) Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry 77:1025–1029

    Article  PubMed  CAS  Google Scholar 

  35. Miskinyte S, Butler MG, Herve D, Sarret C, Nicolino M, Petralia JD, Bergametti F, Arnould M, Pham VN, Gore AV, Spengos K, Gazal S, Woimant F, Steinberg GK, Weinstein BM, Tournier-Lasserve E (2011) Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am J Hum Genet 88:718–728

    Article  PubMed  CAS  Google Scholar 

  36. Muller CR, Ehninger G, Goldmann SF (2003) Gene and haplotype frequencies for the loci hLA-A, hLA-B, and hLA-DR based on over 13,000 german blood donors. Hum Immunol 64:137–151

    Article  PubMed  Google Scholar 

  37. Oudshoorn M, Horn PA, Tilanus M, Yu N (2007) Typing of potential and selected donors for transplant: methodology and resolution. Tissue Antigens 69(Suppl 1):10–12

    Article  PubMed  Google Scholar 

  38. Park MH, Hong SH, Wang K-C (2010) HLA studies in Moyamoya disease. In: Cho BK, Tominaga T (eds) Moyamoya disease update. Springer, New York, pp 54–60

    Chapter  Google Scholar 

  39. Parums DV, Brown DL, Mitchinson MJ (1990) Serum antibodies to oxidized low-density lipoprotein and ceroid in chronic periaortitis. Arch Pathol Lab Med 114:383–387

    PubMed  CAS  Google Scholar 

  40. Parums DV, Dunn DC, Dixon AK, Mitchinson MJ (1990) Characterization of inflammatory cells in a patient with chronic periaortitis. Am J Cardiovasc Pathol 3:121–129

    PubMed  CAS  Google Scholar 

  41. Roder C, Nayak NR, Khan N, Tatagiba M, Inoue I, Krischek B (2010) Genetics of moyamoya disease. J Hum Genet 55:711–716

    Article  PubMed  Google Scholar 

  42. Roder C, Peters V, Kasuya H, Nishizawa T, Takehara Y, Berg D, Schulte C, Khan N, Tatagiba M, Krischek B (2010) Polymorphisms in TGFB1 and PDGFRB are associated with Moyamoya disease in European patients. Acta Neurochir (Wien) 152:2153–2160

    Article  Google Scholar 

  43. Roder C, Peters V, Kasuya H, Nishizawa T, Takehara Y, Berg D, Schulte C, Khan N, Tatagiba M, Krischek B (2011) Common genetic polymorphisms in moyamoya and atherosclerotic disease in Europeans. Childs Nerv Syst 27:245–252

    Article  PubMed  Google Scholar 

  44. Roder C, Peters V, Kasuya H, Nishizawa T, Wakita S, Berg D, Schulte C, Khan N, Tatagiba M, Krischek B (2011) Analysis of ACTA2 in European Moyamoya disease patients. Eur J Paediatr Neurol 15:117–122

    Article  PubMed  Google Scholar 

  45. Sakurai K, Horiuchi Y, Ikeda H, Ikezaki K, Yoshimoto T, Fukui M, Arinami T (2004) A novel susceptibility locus for moyamoya disease on chromosome 8q23. J Hum Genet 49:278–281

    Article  PubMed  CAS  Google Scholar 

  46. Takagi Y (2010) Vascular smooth muscle cell-related molecules and cells. In: Cho BK, Tominaga T (eds) Moyamoya disease update. Spinger, Heidelberg, pp 69–72

    Chapter  Google Scholar 

  47. Takagi Y, Kikuta K, Nozaki K, Hashimoto N (2007) Histological features of middle cerebral arteries from patients treated for Moyamoya disease. Neurol Med Chir (Tokyo) 47:1–4

    Article  Google Scholar 

  48. Yamamoto M, Aoyagi M, Tajima S, Wachi H, Fukai N, Matsushima Y, Yamamoto K (1997) Increase in elastin gene expression and protein synthesis in arterial smooth muscle cells derived from patients with Moyamoya disease. Stroke 28:1733–1738

    Article  PubMed  CAS  Google Scholar 

  49. Yamauchi T, Tada M, Houkin K, Tanaka T, Nakamura Y, Kuroda S, Abe H, Inoue T, Ikezaki K, Matsushima T, Fukui M (2000) Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 31:930–935

    Article  PubMed  CAS  Google Scholar 

  50. Yonekawa Y, Fandimo J, Hug M, Wiesli M, Fujioka M, Khan N (2010) Moyamoya angiopathy in Europe. In: Cho BK, Tominaga T (eds) Moyamoya disease update. Springer, New York

    Google Scholar 

  51. Yonekawa Y, Khan N (2003) Moyamoya disease. Adv Neurol 92:113–118

    PubMed  Google Scholar 

  52. Yonekawa Y, Ogata N, Kaku Y, Taub E, Imhof HG (1997) Moyamoya disease in Europe, past and present status. Clin Neurol Neurosurg 99(Suppl 2):S58–S60

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are thankful to Mr. J.C. Schwitalla, Ms. B. Lyss and Mr. B. Lappenkueper-Schaetz (Centre for Clinical Trials and Studies, Alfried-Krupp-Hospital, Essen, Germany) and to Ms. Sylke Hannemann for important help. Moreover, we thank our patients for participating in this study.

Conflicts of interest

M.K. has received grants, travel expenses and honoraria for lectures and/or educational activities from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis Pharma and Teva Pharmaceutical Industries. Nevertheless, the study design and results are not influenced by commercial interests.

Author information

Authors and Affiliations

  1. Department of Neurology, Alfried-Krupp-von Bohlen und Halbach Hospital, Alfried-Krupp-Straße 21, 45117, Essen, Germany

    Markus Kraemer, Rolf R. Diehl & Peter Berlit

  2. Institute for Transfusion Medicine, University Hospital Essen, Virchowstraße 179, 45147, Essen, Germany

    Peter A. Horn & Falko M. Heinemann

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

    Constantin Roder

  4. Moyamoya Clinic, Children’s Hospital Zurich, University Clinic of Zurich, Steinwiesstraße 75, 8032, Zurich, Switzerland

    Nadia Khan

Authors
  1. Markus Kraemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter A. Horn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Constantin Roder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nadia Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rolf R. Diehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter Berlit
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Falko M. Heinemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Markus Kraemer.

Additional information

Comment

Kraemer et al. analysed the DNA of 33 Caucasian patients with Moyamoya angiopathy for HLA markers. Significant association was observed for HLA-DRB1*03 and HLADRB1*13 in all 33 patients with Moyamoya angiopathy. Moreover, HLA-A*02; HLA-B*08, and HLADQB1*03 frequencies were higher in all patients with Moyamoya angiopathy when compared with the controls. The results of this study indicate a putative association of HLA markers with Moyamoya angiopathy in Caucasian patients. As discussed in this manuscript, in Asian patient cohorts several HLA markers were already reported to be associated with moyamoya disease (MMD), but in Caucasians very little is known about genetic susceptibility of MMD. This study shows several HLA markers which are associated with MMD. Frequency of MMD in Asian and Caucasians are different. This study has an important role in qualifying the genetic mechanism of MMD in Caucasian patients.

Yasushi Takagi

Kyoto, Japan

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kraemer, M., Horn, P.A., Roder, C. et al. Analysis of human leucocyte antigen genes in Caucasian patients with idiopathic Moyamoya angiopathy. Acta Neurochir 154, 445–454 (2012). https://doi.org/10.1007/s00701-011-1261-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00701-011-1261-5

Keywords

Search

Navigation