Genetic Variation in Factor IX and Thrombosis Risk

描述(由申请人提供)：血浆因子IX(f-IX)水平影响血栓形成风险。来自特发性血栓形成遗传学分析(GATIT)项目的最新发现表明：1)血栓形成风险的群体变异具有很高的遗传度(H2)，等于或等于60%，主要是由于未知的遗传因素；2)这些可遗传因素中的很大一部分通过调节中间止血特征(如f-IX)来影响血栓形成的风险；3)f-IX水平的变化还涉及完全未知的实质性遗传成分(H2约40%)；4)血栓形成风险与f-IX水平的遗传相关性很强(Rho[subg]约60%)，表明多个f-IX数量性状基因座(QTL)也影响血栓形成风险。这些发现支持了我们的建议，因为许多这些QTL可能位于f-IX基因座本身，因为该蛋白的表达在转录和转录后水平上主要是通过涉及必要基因区域中的元件的分子事件来调节的。事实上，两个f-IX顺式元件，一个在启动子(AE-5‘)中，一个在3’-UTR(AE-3‘)中，是导致f-IX水平随年龄增加的原因。这意味着f-ix水平的某些人群变化可能与年龄有关。由于我们发现这两个AGE元件都是多态的，在AE-5‘中有G-793A，在AE-3’中有一个二核苷酸重复(DNR)，这些变异是影响f-IX水平和血栓形成风险的候选QTL。我们的假设是，这些变异与f-IX编码区多态(A23387G)一起调节f-IX水平和/或催化活性，从而影响血栓形成的风险。目的1：确定位于基本f-IX启动子元件内的单核苷酸(SNP)G-793A是否影响f-IX水平和血栓易感性。目的2：确定位于3‘-非翻译区(3’-UTR)调控元件的多态DNR是否影响f-IX基因的稳定性、血浆f-IX水平和血栓形成风险。目的3：确定A23387G是否影响f-IX激活率、血浆f-IX水平和血栓形成风险。 我们的长期目标是通过提高我们对血栓形成遗传易感性的理解，提供更准确的诊断方法，包括临床前的皮试，并最终为确定影响止血的相互作用因素作为更有效、更安全的抗凝剂和抗血栓药的潜在治疗靶点提供基础。

DESCRIPTION (provided by applicant): Plasma factor IX (f-IX) levels influence thrombosis risk. Recent discoveries from the Genetics Analysis of Idiopathic Thrombophilia (GAIT) Project demonstrate that: 1) the population variation in thrombosis risk has a high heritability (h2), equal to or > 60%, largely due to unknown genetic factors; 2) a substantial portion of these heritable factors influence thrombosis risk by modulating intermediate hemostasis traits like f-IX; 3) the variation in f-IX levels also involves a substantial genetic component (h2 about 40%) that is entirely unknown; and 4) the variation in thrombosis risk and f-IX levels are strongly correlated genetically (rho[sub g] about 60%), indicating a number of the f-IX quantitative trait loci (QTLs) also influence thrombosis risk. These findings strengthen our proposal because a number of these QTLs are likely to reside in the f-IX locus itself as the expression of this protein is largely regulated at transcriptional and post-transcriptional levels through molecular events involving elements in essential gene regions. Indeed, two f-IX cis-elements, one in the promoter (AE-5') and one in the 3'-UTR (AE-3'), are responsible for the increase in f-IX levels with age. This implies that some of the population variation in f-IX levels may be age-related. Since we found that both age-elements are polymorphic, G-793A in AE-5' and a dinucleotide repeat (DNR) in AE-3', these variations are candidate QTL for f-IX levels and thrombosis risk. Our hypothesis that these variations, along with a f-IX coding region polymorphism (A23387G), modulate f-IX levels and/or catalytic activity, and therefore influence thrombosis risk leads to these Aims: Aim 1: To determine if a single nucleotide (SNP), G-793A, located within an essential f-IX promoter element influences f-IX levels and thrombosis susceptibility. Aim 2: Determine if a polymorphic DNR, which is located in a regulatory element in the 3' -untranslated region (3' -UTR), influences f-IX mRNA stability, plasma f-IX levels and thrombosis risk. Aim 3: Determine if A23387G, a f-IX coding SNP non-conservatively substituting an alanine (Ala) residue for a conserved threonine (thr), influences the rate of f-IX activation, plasma f-IX levels and thrombosis risk. Our long-range goal is to provide more accurate diagnostic approaches, including pre-clinical pedisposition testing, by improving our understanding of the inherited liability to thrombosis, and ultimately to supply the foundation for identifying the interacting factors influencing hemostasis as potential therapeutic targets for more efficacious and safer anticoagulants and antithrombotic agents.