Genomic Approach to Gene Discovery in Thrombophilia

血栓形成倾向基因发现的基因组方法

• 批准号: 8309800
• 负责人: EDWIN Gladstone BOVILL
• 金额: $ 21.06万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309800
• 关键词: Acute; Adverse effects; Affect; Atherosclerosis; Bioinformatics; Biological; Biometry; Blood Vessels; Candidate Disease Gene; Cell Culture Techniques; Chronic; Coagulation Process; Collaborations; Complex; DNA Resequencing; Data Set; Databases; Disease; Disease susceptibility; Endothelial Cells; Environmental Risk Factor; Epidemiology; Event; Family; Family Study; Family member; France; Funding; Genes; Genetic; Genetic Epistasis; Genetic Risk; Genomics; Goals; Gold; Heritability; Heterogeneity; Individual; Investigation; Life; Link; Medicine; Modeling; Mutation; Netherlands; Other Genetics; Pathway interactions; Patients; Physicians; Population; Prophylactic treatment; Protein C; Reaction; Research Personnel; Risk; Role; SNP genotyping; Sampling; Surface; Susceptibility Gene; Thrombophilia; Thrombosis; Universities; Validation; Variant; Veins; Venous Thrombosis; Vermont; base; case control; college; design; effective therapy; gene discovery; gene interaction; genetic pedigree; genetic risk factor; improved; kindred; member; programs; prospective; research study; thrombolysis; treatment duration

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.

在项目6(前身为项目2)中，我们一直在大规模、广泛地研究基因与基因的相互作用 (n=800)法裔加拿大人，蛋白C缺乏，嗜血栓家族，我们在其中鉴定了三个 与血栓形成有显著关联的基因组区域。这一血缘关系被证明有一个小的 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 在这个家族中，血栓形成是一种寡源性疾病。少基因疾病提供了有吸引力的模式 研究多基因疾病，与动脉粥样硬化等多基因疾病形成对比 易感基因众多，每一个影响都很小。在这个家族中，血栓形成的剩余遗传性 0.40，在校正了蛋白C突变的遗传性后，表明未知的易感性 基因(S)的作用大小与蛋白C相同。因此，未知基因(S)的作用 应该是现代基因组策略可以检测到的。在推行这一战略的过程中，我们重新排序了109个 与血栓形成相关的三个基因组区域内的候选基因(约占这些区域中基因的50% 地区)使用病例对照设计。在我们对这个丰富的数据库进行初步分析时，使用SNP基因分型 基于通过重新测序确定的SNPs，我们发现了一个有吸引力的 候选基因的遗传流行病学分析与初步表型证实 比较受影响家庭成员培养的内皮细胞与正常内皮细胞的微阵列实验 控制。这个项目的目标是：1)彻底分析人类基因组中重新测序的基因数据库 佛蒙特州家族与日益复杂的相互作用易感基因等级有关，2) 在独立的种群中验证这些发现，3)将我们的研究扩展到生物途径 由佛蒙特州亲属中确定的个人候选基因牵连的情况下， 在家庭数据集的分析中发现的SNP不会在使用 类似的SNP基因分型和重新测序方法以及4)改进风险分析，以便处于 由于已确定的遗传风险因素而导致的血栓形成风险增加可以获得适当的强度和 预防和急性事件的治疗持续时间。作为候选基因和生物途径 他们暗示，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：这项研究将提高个别医生预测个别患者风险的能力 在他们的血管中形成威胁生命的凝块，从而允许更有效地治疗这种生命 有威胁的疾病。它还将减少由损害引起的严重慢性副作用的数量。 到含有凝块的血管。