Original article Analysis of TGFB1 in European and Japanese Moyamoya disease patients Chao Liu a, b,1 , Constantin Roder a,1 , Claudia Schulte c , Hidetoshi Kasuya d , Hiroyuki Akagawa e , Tsutomu Nishizawa f , Taku Yoneyama d , Yoshikazu Okada d , Nadia Khan g , Marcos Tatagiba a , Daniela Berg h , Boris Krischek a, * a Department of Neurosurgery, University of Tübingen, Tübingen, Germany b Department of Neurosurgery, 2nd Hospital of Jilin University, Changchun, China c The Hertie-Institute for Clinical Brain Research, Department of Neurodegeneration and German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany d Department of Neurosurgery, Medical Center East, Tokyo Women’s Medical University, Tokyo, Japan e Tokyo Women’s Medical University, Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan f Division of Virology, Department of Infection and Immunity, Jichi Medical School, Shimotsuke, Japan g Moyamoya Clinic, Children’s University Hospital Zürich, Zürich, Switzerland h Center of Neurology, Department of Neurodegeneration, University of Tübingen, Tübingen, Germany article info Article history: Received 29 September 2011 Received in revised form 5 May 2012 Accepted 5 May 2012 Available online 1 June 2012 Keywords: Genetics Growth factors Moyamoya disease Single nucleotide polymorphism TGFB1 abstract Background: Despite large efforts in researching the genesis of Moyamoya disease (MMD), the etiology of this rare disease remains widely unknown. In a previous publication we described two genetic variants in the first exon of transforming growth factor beta 1 (TGFB1) which were associated and showed a tendency toward significance, respectively. In this study we performed a follow-up analysis of TGFB1 by sequencing the complete exon 1 in European and by genotyping previously described positively asso- ciated single nucleotide polymorphisms (SNPs) in Japanese patients with MMD. Methods: The complete first exon of TGFB1 was genotyped in 40 MMD patients and 68 healthy controls from central Europe. For verification, genotyping of the previously described SNPs rs1800470 and rs1800471 was performed in 45 Japanese MMD patients and 79 healthy controls. Analysis was performed by capillary sequencing with custom made primers. Results: Sequencing of the first exon of TGFB1 in the European cohort did not reveal any new disease- associated nor other genetic variations. The previously described disease association of rs1800471 and tendency toward significance of rs1800470 could not be replicated in the Japanese cohort. Conclusions: As no new genetic variants were uncovered in this study of the first exon of TGFB1 in European MMD patients and because of the negative association of rs1800470 and rs1800471 in Japanese MMD patients, a role of this exon of TGFB1 in the genesis of MMD is unlikely. Further analyses with even larger cohorts may be necessary to detect causal genetic factors that contribute to the genesis of this disease. Ó 2012 Elsevier Masson SAS. All rights reserved. 1. Introduction Moyamoya disease (MMD) is defined as a bilateral stenosis of the terminal portions of the internal carotid arteries (ICAs) accompanied by diffuse abnormal vessels which bypass the stenosis. The term “Moyamoya” is Japanese and describes a “puff of smoke” resembling the angiographic findings of diffuse fine collaterals. Clinical presentation of patients varies from symptoms such as headaches, transient ischemic attacks, epileptic seizures or disturbances of speech and cognition to severe neurological conditions with ischemic or hemorrhagic stroke. Epidemiological data show two peaks of clinical manifestation at 5e10 and 30e40 years of age, as well as a much higher incidence in Asian coun- tries (mainly in Japan and Korea with approximately 1 per 100.000 in Japan) than in non-Asian countries (approximately 0.1 per 100.000). Although the first description of this disease entity was more than 50 years ago, the etiology of MMD is still widely unknown [13, 15]. Major efforts have been put into the research of histopathological changes, variations in biological messenger molecules as well as genetic analysis [1, 13]. In a recent study we combined the above mentioned techniques and analyzed single nucleotide polymorphisms (SNPs) in potential candidate genes that * Corresponding author. Division of Neurosurgery, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada. Tel.: þ1 416 301 9927; fax: þ1 416 913 1131. E-mail address: krischek@gmail.com (B. Krischek). 1 Authors contributed equally to this work. Contents lists available at SciVerse ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg 1769-7212/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmg.2012.05.002 European Journal of Medical Genetics 55 (2012) 531e534