Genomic Approach to Gene Discovery in Thrombophilia

在项目6（以前的项目2）中，我们一直在研究基因-基因相互作用， （n=800）法裔加拿大人、蛋白C缺陷、血栓形成家族，我们已确定其中三个 与血栓形成有显著联系的基因组区域。这一家族已被证明有一个小的 与蛋白C相互作用导致血栓形成的基因数量（一到三个），从而表征 血栓形成倾向是一种寡基因性疾病。寡基因疾病提供了有吸引力的模型， 研究多基因疾病，与动脉粥样硬化等多基因疾病相反， 易感基因众多，每一个基因的作用都很小。在这个家族中，血栓形成的剩余遗传力为 0.40，校正蛋白C突变的遗传力后，表明未知的易感性 基因具有与蛋白C大致相同的作用。因此，未知基因的作用 应该能被现代基因组学检测到在实施这一战略时，我们重新安排了109个 与血栓形成相关的三个基因组区域内的候选基因（这些区域中约50%的基因）， 区域）使用病例对照设计。在我们对这个丰富的数据库的初步分析中，使用SNP基因分型 基于通过重测序确定的SNP，我们已经确定了一个有吸引力的 候选基因通过遗传流行病学分析与初步表型确证， 微阵列实验比较了从受影响的家庭成员和正常家庭成员培养的内皮细胞， 对照本项目的目标是：1）彻底分析基因组中的重测序基因数据库， 佛蒙特州的家庭就越来越复杂的层次相互作用的易感基因，2） 在独立人群中验证这些发现，3）将我们的研究扩展到生物学途径 在佛蒙特州亲属中发现的个体候选基因所暗示的情况下， 在家庭数据集分析中鉴定的SNP在独立人群中没有使用 相似的SNP基因分型和重测序方法和4）改进的风险分析， 由于已确定的遗传风险因素导致的血栓形成风险增加可以得到适当的强度， 预防和急性事件的治疗持续时间。作为候选基因， 他们将与项目中的其他调查人员合作进行调查 项目组。 相关性：本研究将提高个体医生预测个体患者风险的能力 在他们的静脉中形成危及生命的血栓，因此可以更有效地治疗这种生命 威胁疾病它还将减少由损伤引起的严重慢性副作用的数量 到含有凝块的血管。

In Project 6 (formerly Project 2), we have been investigating gene-gene interactions in a large, extended (n=800) French Canadian, protein C deficient, thrombophilic family in which we have identified three genomic regions with significant linkage to thrombosis. This kindred has been demonstrated to have a small number of genes (one to three) interacting with protein C to cause thrombosis, thus characterizing thrombophilia in this family as an oligogenic disease. Oligogenic diseases offer attractive models for investigating multigenic diseases, in contrast to polygenic diseases like atherosclerosis which have numerous susceptibility genes, each of small effect. In this family the remaining heritability for thrombosis of 0.40, after correcting for the heritability of the protein C mutation, suggests that the unknown susceptibility gene(s) have an effect of about the same magnitude as protein C. Thus, the effect of the unknown gene(s) should be detectable by modern genomic strategies. In pursuing this strategy we have resequenced 109 candidate genes within the three genomic regions linked with thrombosis (about 50% of the genes in these regions) using a case control design. In our preliminary analysis of this rich database, using SNP genotyping on additional family members based on SNPs identified by resequencing, we have identified an attractive candidate gene by genetic epidemiological analysis with preliminary phenotypic corroboration from microarray experiments which compared endothelial cells cultured from affected family members with normal controls. The goals of this project are to: 1) thoroughly analyze the database of resequenced genes in the Vermont family with respect to an increasingly complex hierarchy of interacting susceptibility genes, 2) validate these findings in independent populations, 3) extend our investigation to the biological pathways implicated by the individual candidate genes identified in the Vermont kindred in cases where individual SNPs identified in the analysis of the family dataset are not reproduced in independent populations using a similar SNP genotyping and resequencing approach and 4) improve risk profiling so that individuals at increased risk for thrombosis due to identified genetic risk factors can receive appropriate intensity and duration of treatment for prophylaxis and for acute events. As candidate genes and the biological pathways they implicate are identified they will be explored in collaboration with the other investigators in the program project group. Relevance: This study will improve individual physician's ability to predict the risk for an individual patient to develop life threatening clots in their veins and therefore allow for more effective treatment of this life threatening disease. It will also decrease the number of serious chronic side effects that result from damage to the blood vessels which contain the clots.