Genetic variation influencing brain AVM

影响大脑 AVM 的遗传变异

基本信息

批准号：
8049024
负责人：
WILLIAM L YOUNG
金额：
$ 19.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8049024
关键词：
ACVRL1 gene Address Adult Affect Age Alleles Alternative Splicing Amino Acids Area Arteriovenous malformation Biological Process Blood Blood Vessels Brain Candidate Disease Gene Caucasians Caucasoid Race Cavernous Malformation Chromosomes Clinical Clinical Course of Disease Code Collection Complex Copy Number Polymorphism DNA DNA lesion Data Databases Detection Diagnosis Disease Disease susceptibility Doctor of Medicine Enrollment Ethnic group Etiology Evaluation Event Family Frequencies Funding Gender Genes Genetic Genetic Variation Genomics Genotype Germ-Line Mutation Germany Haplotypes Hemorrhage Human Genome Individual Inherited Intracranial Hemorrhages Investigation Knowledge Lesion Literature Maps Measures Medical Messenger RNA Meta-Analysis Methodology Methods Modeling Netherlands Odds Ratio Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Patients Peptide Signal Sequences Phenotype Population Predisposition Prevalence Principal Component Analysis Production Proteins Publishing RNA RNA Splicing Race Rare Diseases Recurrence Reporting Research Research Personnel Sample Size Sampling Siblings Signal Transduction Single Nucleotide Polymorphism Somatic Mutation Specimen Staging Stratification Suggestion Testing Time Tissues Transmembrane Domain Universities Variant Vascular Endothelial Growth Factors Venous Malformation Work base case control cohort disorder risk follow-up genetic association genetic variant genome wide association study genome-wide novel programs protein expression prototype receptor synergism

项目摘要

Reviewer #1: ...importance of genetic factors in formation ofAVMs has never been established... This important point is now carefully addressed in Section 2.3. Although most AVMs are sporadic, there is indeed evidence supporting a familial component. A recent review article identified 53 cases of AVM without Hereditary Hemorrhagic Telangectasia (HHT) in 25 families.39 Further, there has been one linkage and association analysis, which identified seven candidate regions, with the strongest signal at chromosome 6q25 (LOD=1.88; P=0.002).25 This study was unfortunately underpowered due to the small sample size. Further evidence of a genetic component to sporadic AVMs comes from estimation of sibling recurrence risk ratio of disease, an important consideration raised by Reviewer #1. This measure, Sibling, is defined as the risk of disease in siblings of an individual with disease, divided by the population prevalence of the disease.40 Complex diseases display a wide range of Xsibiing values.41'43 Based on the reported literature, we present in Section 2.3 estimates for XSibiing in AVM which are consistent with a genetic contribution to the disease. Taken together, then, there is at least modest evidence supporting familial aggregation for the AVM phenotype, although definitive proof is lacking. Perhaps use of the term "sporadic" also reinforces an unwarranted assumption that no genetic underpinning exists. However, in context of our preliminary and other published data, it seems reasonable to proceed on the notion that genetic variation at least influences the susceptibility and clinical course of the disease. We do not hypothesize that "formation" of AVM lesions is caused by a single genetic locus. Rather, AVM is a complex disease that is likely due to many factors. Even Hereditary Hemorrhagic Telangectasia almost certainly requires some as yet unknown set of modifier genes or factors for the AVM phenotype to be expressed. Variation in such modifier genes may be heritable, e.g., there are multiple genetic loci that appear to control VEGF-induced angle-genesis.60 61 if...AVMs are sporadic, the investigators ... need to [be] searching for somatic genomic variants. Although we believe there is ample evidence for a genetic component in AVM susceptibility, somatic mutation is an excellent suggestion for an alternative mechanism. There is evidence for a "second-hit" model in cavernous malformations6'64 and systemic venous malformations.2'3 As exciting as this hypothesis is, it also presents significant logistical problems for AVMs since we do not know what gene to target, although ENG and ALK-1 might be reasonable candidates. Nonetheless, we agree that it is scientifically important to initiate investigation of somatic genetic variation in AVMs. Therefore, we have made the search for somatic mutations an exploratory aim, adding Doug Marchuk as a Co-investigator, an expert in somatic mutation studies. Candidate gene methodology...given [its] track record ...in complex medical disorders ...is not welljustified. Many of the reviewer's points in this regard are well taken. Accordingly, we have now reshaped the approach to focus on genome-wide association (GWAS). However, we can still leverage our knowledge of plausible candidates in consideration of how we follow up our initial GWAS analyses (see Section 4.8.1.A). The reviewer brought up the important issue of replication. We now emphasize (Section 3.3.1) that we recently provided the first description of a common genetic variant associated with sporadic AVMs: an intronic variant of ALK-1 that was present at a higher frequency in AVM cases compared to healthy controls.81 This association was independently replicated by the group at the University of Bonn. Germany;78 a meta-analysis of combined results was published.79'146 We now provide new preliminary data that this single nucleotide polymorphism (SNP) is associated with alternative splicing (Section 3.3.1), which sets the stage for functional characterization of the effects of this variant on the gene product. Data for candidate genetic variants that predict spontaneous hemorrhage, however, have not been replicated; these results are presented as preliminary data. A longitudinal cohort with an infrequent outcome event (hemorrhage) is far more difficult to obtain with so few research groups active in this area. We would suggest that for a rare disease like AVM, it is not only reasonable but highly constructive to report initial associations of important clinical associations, despite the well-known propensity for false positives. The ALK-1 SNP example given above is a good example of such synergism between different research groups. PHS 398/2590 (Rev.11 /07) Pane 171

评论者＃1： ...遗传因素在avms形成中的重要性从未建立... 现在，第2.3节仔细解决了这一点。尽管大多数AVM都是零星的，但确实，证据支持家族成分。最近的一篇评论文章确定了53例AVM案件 25个家庭中的遗传性出血性特拉吉斯症（HHT）。39此外，还有一个联系关联分析，确定了七个候选区域，在6q25染色体时信号最强（LOD = 1.88; P = 0.002）.25不幸的是，由于样本量较小，这项研究的能力不足。零星AVM的遗传成分的进一步证据来自对兄弟姐妹复发风险的估计疾病之比，审查员1提出的重要考虑因素。该措施（同胞）被定义为风险疾病个体兄弟姐妹的疾病，由疾病的人口流行划分。40 复杂疾病显示了广泛的Xsibiing值。41'43基于报告的文献，我们在第2.3节AVM中Xsibiing的估计值与对该疾病的遗传贡献一致。因此，至少有适度的证据支持AVM的家族聚集表型，尽管缺乏明确的证据。也许使用“零星”一词也加强了没有遗传基础存在的不必要的假设。但是，在我们的初步和其他方面已发表的数据，关于遗传变异至少会影响的观念似乎是合理的疾病的敏感性和临床过程。我们不假设AVM病变的“形成”是由一个遗传基因座引起。相反，AVM是一种复杂的疾病，可能是由于许多因素引起的。甚至遗传性出血性毛te骨几乎可以肯定需要一些尚未知道的修饰基因或表达AVM表型的因素。这种修饰基因的变化可能是可遗传的，例如是多个遗传基因座，似乎可以控制VEGF诱导的角生成。6061 如果... AVM是零星的，则研究人员...需要[]寻找躯体基因组变体。尽管我们认为有足够的证据表明AVM易感性，但体细胞突变是替代机制的绝佳建议。有证据表明在海绵状畸形6'64和全身静脉畸形。2'3像这个假设一样令人兴奋，也很令人兴奋为AVM提出了重大的后勤问题，因为我们不知道要靶向什么基因，尽管ENG和 ALK-1可能是合理的候选人。但是，我们同意发起很重要研究AVM中的体细胞遗传变异。因此，我们已经寻找躯体突变一个探索性的目的，增加了道格·马尔克克（Doug Marchuk）作为躯体突变研究专家的共同投资者。候选基因方法论...给定[它的]往绩...在复杂的医学疾病中...没有很好地证明。在这方面，许多审稿人的观点都很好。因此，我们现在已经重塑了方法专注于全基因组关联（GWAS）。但是，我们仍然可以利用我们对合理的知识考虑到我们如何跟踪我们最初的GWAS分析的候选人（请参阅第4.8.1.A节）。评论者提出了重复的重要问题。我们现在强调（第3.3.1节），我们最近提供了与零星AVM相关的常见遗传变异的第一个描述：ALK-1的内含子变体与健康对照相比，在AVM病例中以更高的频率存在。81该关联是由波恩大学独立复制。德国; 78合并的荟萃分析结果发表了。79'146我们现在提供了新的初步数据，该数据是该单核苷酸多态性（SNP）与替代剪接相关联（第3.3.1节），该剪接为功能奠定了阶段该变体对基因产物的影响的表征。但是，尚未复制预测自发出血的候选遗传变异的数据。这些结果表示为初步数据。纵向队列，有不经常的结果事件（出血）很难获得该领域的研究组很难获得。我们建议对于像AVM这样的罕见疾病，报告的初始关联不仅是合理的，而且具有高度的建设性尽管有众所周知的假阳性倾向，但重要的临床关联。 ALK-1 SNP示例上面给出的是不同研究小组之间这种协同作用的一个很好的例子。 PHS 398/2590（Rev.11 /07）窗格171