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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 associated 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., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

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.

The European form of Moyamoya disease clearly differs from the Asian form. Clinically the timing of vasculopathy onset and a lower rate of hemorrhage are striking as compared to the Asian Moyamoya disease.Single nucleotide polymorphisms that play a role in atherosclerosis, vascular growth and transformation processes have been found to be associated with the European form. Candidate gene associations found in Asian patients could not be replicated in European patients.To elucidate the characteristics, we describe the clinical features as well as the genetic findings that we have found in our combined cohorts of European patients.

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with approximately 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 x 10(-12)), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 x 10(-9)) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 x 10(-9)). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 x 10(-12)) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 x 10(-22)). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.