The molecular pathogenesis of intracranial aneurysms and subarachnoid hemorrhage

颅内动脉瘤和蛛网膜下腔出血的分子发病机制

• 批准号: 518892379
• 负责人: Privatdozent Dr. Georg Rosenberger, Ph.D.
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/518892379?language=en
• 关键词: molecular; pathogenesis; intracranial; aneurysms; subarachnoid

The prevalence of intracranial aneurysms (IA) is around 3% in the general population. Unruptured IAs (UIAs) are associated with a risk for rupture and subsequent aneurysmal subarachnoid hemorrhage (aSAH) which is characterized by a high mortality. The risk for UIA and aSAH is increased among patient’s family members. Thus, a genetic basis of IA/aSAH is obvious; however, it is poorly understood. Although several large exome/genome wide association studies and exome sequencing (ES) studies identified various risk loci and candidate genes, respectively, valid disease genes have not been described. This may be due to technical limitations of sequencing technologies, a genetically complex architecture of the disease (digenic/oligogenic inheritance) or somatic sequence alterations causing UIA/aSAH. Therefore, the main goal of this study is to solve the missing hereditability problem for UIA and aSAH. We established a cohort comprising 115 individuals either with a familial history of UIA/aSAH or with a substantial sporadic manifestation. We performed short-read ES in 37 unrelated patients (31 sporadic and 6 familial cases) and 10 affected family members (from the familial cases). By using a family-based approach (filtering for variants shared by affected family members) and sequencing of further affected individuals, we defined novel candidate risk variants in the genes EDIL3 and TAGLN, both of which encoding proteins that are strongly involved in vascular biology. Now, we aim to characterize the functional consequences of the identified sequence variants in EDIL3 and TAGLN in order to determine their relevance in the pathogenesis of UIA/aSAH. In parallel, we intend to expand our study: (i) We are going to perform ES in the rest of our cohort to increase the number of individual datasets that can be evaluated (this is crucial e.g. for statistical evaluations); in addition, genome-wide sequencing is to be carried out in three affected families. (ii) We adapt our bioinformatics pipeline and filter for altered genes which are enriched in our sub-cohort of unrelated patients (gene-based approach); in order to generate larger cohorts, we cooperate with other consortia. (iii) We will analyze paired-sample ES data (blood vs. aneurysmal tissue) to identify somatic variants. (iv) By performing thorough variant association testing (gene burden/non-burden tests) and gene×gene interaction testing with ES data we aim to uncover possible digenic and oligogenic inheritance; we also cooperate with other consortia for this. (v) We will carry out gene product-matched assays to characterize functional impact of identified sequence variants on vascular biology. Taken together, the results from our study should improve the management of UIA and risk stratification for aSAH in a routine clinical setting.

一般人群中颅内动脉瘤（IA）的患病率约为3%。未破裂的IA（UIA）与破裂和随后的蛛网膜下腔出血（aSAH）风险相关，aSAH的特征是死亡率高。UIA和aSAH的风险在患者的家庭成员中增加。因此，IA/aSAH的遗传基础是显而易见的;然而，对其了解甚少。尽管几个大的外显子组/全基因组关联研究和外显子组测序（ES）研究分别鉴定了各种风险基因座和候选基因，但尚未描述有效的疾病基因。这可能是由于测序技术的技术限制、疾病的遗传复杂结构（双基因/寡基因遗传）或引起UIA/aSAH的体细胞序列改变。因此，本研究的主要目标是解决UIA和aSAH的遗传性缺失问题。我们建立了一个队列，包括115名有UIA/aSAH家族史或有大量散发表现的个体。我们对37例无关患者（31例散发性和6例家族性病例）和10名受累家庭成员（来自家族性病例）进行了短读ES。通过使用基于家族的方法（过滤受影响家族成员共享的变体）和进一步受影响个体的测序，我们在基因EDIL 3和TAGLN中定义了新的候选风险变体，这两种基因编码与血管生物学密切相关的蛋白质。现在，我们的目标是表征EDIL 3和TAGLN中鉴定的序列变体的功能后果，以确定它们在UIA/aSAH发病机制中的相关性。与此同时，我们打算扩大我们的研究：（i）我们将在我们队列的其余部分中进行ES，以增加可以评估的个体数据集的数量（这对于统计评估至关重要）;此外，将在三个受影响的家庭中进行全基因组测序。(ii)我们调整了我们的生物信息学管道，并过滤了在我们的不相关患者子队列中富集的改变基因（基于基因的方法）;为了生成更大的队列，我们与其他财团合作。(iii)我们将分析配对样本ES数据（血液与淋巴组织）以识别体细胞变异。(iv)通过使用ES数据进行全面的变异关联测试（基因负担/非负担测试）和基因×基因相互作用测试，我们的目标是发现可能的双基因和寡基因遗传;我们还为此与其他财团合作。(v)我们将进行基因产物匹配试验，以表征已鉴定序列变异体对血管生物学的功能影响。综上所述，我们的研究结果应该改善UIA的管理和aSAH在常规临床环境中的风险分层。