NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation
NOTCH4 gene polymorphisms as potential risk factors for brain arteriovenous malformation development and hemorrhagic presentation
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DOI：
10.3171/2016.3.jns151731
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发表时间：
2017-05-01
影响因子：
4.1
通讯作者：
Simon, Matthias
中科院分区：
文献类型：
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作者：
Delev, Daniel;Pavlova, Anna;Simon, Matthias
目的脑动静脉畸形(Avms)是青壮年颅内出血常见而重要的原因。目前对AVM发生的分子遗传学发病机制知之甚少。Notch家族的基因控制着血管的正常发育和适当的动静脉规范。组成性表达活性NOTCH4的转基因小鼠常发生动静脉曲张。本研究旨在探讨NOTCH4基因多态性与脑动静脉畸形的形成和临床表现的关系。方法采用聚合酶链式反应和DNA直接测序或限制性内切酶消化的方法，对153例脑动静脉畸形患者和192例健康对照(即献血者)进行了NOTCH4基因10个单核苷酸多态性(SNPs)的基因分型。129例患者均有相关的临床资料。采用单变量和多变量的单标记和探索性单倍型分析，以确定AVM发生和出血性或癫痫的潜在遗传危险因素。结果AVM患者中发现11个由3-4个SNP组成的单倍型(大多数位于NOTCH4基因的表皮生长因子样域)，其频率显著高于对照组。单因素分析显示rs443198_TT和rs915895_AA两种基因型均与出血量显著相关，rs1109771_GG基因型与癫痫相关。多因素回归分析显示，rs443198_TT与动静脉畸形出血有显著相关性。结论NOTCH4基因可能是动静脉动静脉畸形发病和临床表现的遗传危险因素，NOTCH4在动静脉动静脉畸形的发病机制中起一定作用。
OBJECTIVE Arteriovenous malformations (AVMs) of the brain are a frequent and important cause of intracranial hemorrhage in young adults. Little is known about the molecular-genetic pathomechanisms underlying AVM development. Genes of the NOTCH family control the normal development of vessels and proper arteriovenous specification. Transgenic mice with constitutive expression of active NOTCH4 frequently develop AVMs. Here, the authors report a genetic association study investigating possible associations between NOTCH4 gene polymorphisms and formation and clinical presentation of AVMs.METHODS After PCR amplification and direct DNA sequencing or restriction digests, 10 single-nucleotide polymorphisms (SNPs) of the NOTCH4 gene were used for genotyping 153 AVM patients and 192 healthy controls (i.e., blood donors). Pertinent clinical data were available for 129 patients. Uni- and multivariate single-marker and explorative haplotype analyses were performed to identify potential genetic risk factors for AVM development and for hemorrhagic or epileptic presentation.RESULTS Eleven calculated haplotypes consisting of 3-4 SNPs (most of which were located in the epidermal growth factor like domain of the NOTCH4 gene) were observed significantly more often among AVM patients than among controls. Univariate analysis indicated that rs443198_TT and rs915895_AA genotypes both were significantly associated with hemorrhage and that an rs1109771_GG genotype was associated with epilepsy. The association between rs443198_TT and AVM bleeding remained significant in the multivariate regression analysis.CONCLUSIONS The authors' results suggest NOTCH4 SNPs as possible genetic risk factors for the development and clinical presentation of AVMs and a role of NOTCH4 in the pathogenesis of this disease.