Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders.
Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders.
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描述止血组作为对血栓和出血性疾病的遗传基础进行个体化分析的辅助手段。
DOI：
10.1007/s00439-011-0984-y
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发表时间：
2011
期刊：
影响因子：
5.3
通讯作者：
Cooper,DavidN
中科院分区：
文献类型：
--
作者：
Fechtel,Kim;Osterbur,MarikaL;Kehrer-Sawatzki,Hildegard;Stenson,PeterD;Cooper,DavidN
下一代测序和全基因组关联研究是识别人群中赋予疾病风险的遗传变异的有力工具。然而，就其本身而言，它们无法提供关于这些变异如何有助于表现出复杂遗传的疾病的个体风险的见解，或者在给定个体中赋予健康。即使在具有显著疾病风险的良好特征的变体的情况下，也有更多的健康个体携带该变体，而没有明显的不良影响，而不是那些表现出疾病的人。获得低成本的基因组序列数据有望提供对复杂疾病遗传成分性质的前所未有的详细了解，但需要对患有和未患有疾病的个体的序列数据进行大规模比较，以提供临床校准。提供信息学支助仍然存在问题，因为目前没有办法解释所产生的数据。在这里，我们开始这个过程，这样一个研究的先决条件，通过缩小从一个完整的基因组到一个单一的生物系统的重点。为此，我们研究了“止血酶体”，更具体地说，我们关注与已知影响止血和血栓形成的人类基因相关的DNA序列变化，这些基因可以协同分析，并在个体基础上，询问变异体的特定组合如何发挥作用以赋予疾病易感性。作为第一步，我们描绘已知的成员的止血酶组和探索的性质，可能会导致疾病的个体，其止血平衡已成为向血栓形成前或抗凝表型转移的遗传变异。
Next-generation sequencing and genome-wide association studies represent powerful tools to identify genetic variants that confer disease risk within populations. On their own, however, they cannot provide insight into how these variants contribute to individual risk for diseases that exhibit complex inheritance, or alternatively confer health in a given individual. Even in the case of well-characterized variants that confer a significant disease risk, more healthy individuals carry the variant, with no apparent ill effect, than those who manifest disease. Access to low-cost genome sequence data promises to provide an unprecedentedly detailed view of the nature of the hereditary component of complex diseases, but requires the large-scale comparison of sequence data from individuals with and without disease to deliver a clinical calibration. The provision of informatics support remains problematic as there are currently no means to interpret the data generated. Here, we initiate this process, a prerequisite for such a study, by narrowing the focus from an entire genome to that of a single biological system. To this end, we examine the ‘Hemostaseome,’ and more specifically focus on DNA sequence changes pertaining to those human genes known to impact upon hemostasis and thrombosis that can be analyzed coordinately, and on an individual basis, to interrogate how specific combinations of variants act to confer disease predisposition. As a first step, we delineate known members of the Hemostaseome and explore the nature of the genetic variants that may cause disease in individuals whose hemostatic balance has become shifted toward either a prothrombotic or anticoagulant phenotype.