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Polymorphisms in TGFB1 and PDGFRB are associated with Moyamoya disease in European patients

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Abstract

Background

The etiology of Moyamoya disease (MMD) is still widely unknown. Several publications on Moyamoya describe differences of cytokine and growth factor concentrations in different specimen. We analyzed the DNA of patients with MMD for single nucleotide polymorphisms (SNPs) in and upstream of the genes for previously described associated cytokines and growth factors.

Method

Thirteen SNPs were genotyped in or upstream to four genes—basic fibroblast growth factor (BFGF), cellular retinoic acid-binding protein 1 (CRABP1), platelet derived growth factor receptor beta (PDGFRB), and transforming growth factor beta 1 (TGFB1)—comparing 40 DNA samples of MMD patients to 68 healthy controls from central Europe. Genotyping was performed by sequencing the SNP-containing genetic regions with custom made primers.

Findings

We found association of two SNPs: rs382861 [A/C] (p = 0.0373, OR = 1.81, 95% CI = 1.03–3.17) in the promoter region of PDGFRB and rs1800471[C/G] (p = 0.0345, OR = 7.65, 95% CI = 0.97–59.95), located in the first exon of TGFB1.

Conclusion

Our results indicate possible genetic risk factors for the genesis of MMD. TGFB1 and PDGFRB are involved in vascular growth and transformation processes which may play a role in the development of MMD. Further analyses in larger European cohorts and replication in patients of different ethnicity, as well as functional studies, may lead to possible early detection of patients at risk for developing MMD and subsequently to future preventive therapies.

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Acknowledgements

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

Conflicts of interest/disclosures

None

Author information

Authors and Affiliations

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

    Constantin Roder, Vera Peters, Marcos Tatagiba & Boris Krischek

  2. Division of Neurosurgery, Medical Center East, Tokyo Women’s Medical University, Tokyo, Japan

    Hidetoshi Kasuya

  3. International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan

    Tsutomu Nishizawa & Yayoi Takehara

  4. Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research and German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany

    Daniela Berg & Claudia Schulte

  5. Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA

    Nadia Khan

Authors
  1. Constantin Roder
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  2. Vera Peters
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  3. Hidetoshi Kasuya
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  4. Tsutomu Nishizawa
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  5. Yayoi Takehara
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  6. Daniela Berg
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  7. Claudia Schulte
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  8. Nadia Khan
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  9. Marcos Tatagiba
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  10. Boris Krischek
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Corresponding author

Correspondence to Boris Krischek.

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Comment

It was 19 years ago, when the first symposium on the etiology of Moyamoya disease (MMD) was held at Tokyo within the scope of Research Committee Meeting of the spontaneous occlusion of the circle of Willis sponsored by Ministry of Health and Welfare, Japan and partly sponsored by the Shimizu Foundation of Immunological Research. On the occasion, Ogata N et al. overviewed the topic and summarized application of molecular biological techniques as follows:(1) Studies on the growth factors related to intimal cell proliferation. (2) Application of restricted fragment length polymorphism (RFLP) linkage analysis. And (3) establishment of an animal model [1]. Recently, one of the subjects is well overviewed by Takagi Y in the book just appeared "Moyamoya disease Update" (Springer 2010) [2].

Roder C et al. studied here after a while the above mentioned growth factors and analyzed 13 SNPs in or upstream to four genes (bFGF, CRABP1, PDGFRB, TGFB1) comparing 40 DNA samples of MMD patients to 68 healthy controls from central Europe. Their results indicate possible participation of genetic risk factors namely PDGFRB and TGFB1 for the genesis of MMD. As the authors indicated, however, this study's expressiveness was limited by the small number of cases as well as the hypothetical picking of SNPs. But this is an important report, because this study was based on one of the largest cohorts of MMD samples examined in Europe to date. In further studies, it is expected that possible differences of genetic background between Europe and Asia will be analyzed.

By the way, one should be careful in such analysis on ethnics of cases and pureness or uniformity of the disease; besides Caucasians, around 10% of Moyamoya cases in Europe originate from Asia and Middle East. Furthermore, Moyamoya syndrome seems to be more prevalent in Europe than in Japan[3].

Yasushi TAKAGI (Fukui-Kyoto)

Yasuhiro YONEKAWA (Zürich)

References

1. Ogata N, Yonekawa Y, Gotoh Y: History of research on the etiology of spontaneous occlusion of the circle of Willis. In Yonekawa Y (ed): Annual Report 1991 of the Research Committee of spontaneous occlusion of the circle of Willis (incl, Proceeding of Symposium on the Etiology of Spontaneous Occlusion of the circle of Willis (Moyamoya disease)). Osaka, 1992, pp114–117 (Jpn with Eng abstract)

2. Takagi Y: Vascular smooth muscle cell-related molecules and cells. In Cho BK,Tominaga T(eds) Moyamoya Disease Upate. Springer, 2010, Tokyo. pp69-72

3. Yonekawa Y, Fandino J, Hug M et al. : Moyamoya angiopathy in Europe. In ditto pp361-369

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Roder, C., Peters, V., Kasuya, H. et al. Polymorphisms in TGFB1 and PDGFRB are associated with Moyamoya disease in European patients. Acta Neurochir 152, 2153–2160 (2010). https://doi.org/10.1007/s00701-010-0711-9

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  • DOI: https://doi.org/10.1007/s00701-010-0711-9

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