STATISTICAL GENETICS OF PDGF RELATED PHENOTYPES

描述(改编自《调查者摘要》)：血小板和 血小板产品，如血小板衍生生长因子(PDGF)，是 对维持止血至关重要，并不断牵连 在动脉粥样硬化形成中。然而，人们对基因的了解很少 血小板生物学中正常数量变异的测定。这个 这项拟议研究的总体目标是检测基因的影响 血小板衍生生长因子等性状的正常生物变异 在非人类灵长类动物模型中影响其可用性和活性的因素 治疗动脉粥样硬化。将使用统计遗传方法来检测 并测量未知主要基因座的变异的影响，已知的 候选基因座、匿名微卫星基因座和多基因 血小板储存的PDGF及其他PDGF相关物质的数量变化 特征。这些特征包括血小板数量和体积，血清 血小板活化因子(PAF)、血浆血栓素B2、血清胰岛素 如生长因子-1(IGF-1)、总高密度脂蛋白 胆固醇，将在600只纯种狒狒身上进行测量。每只动物的 6个候选多态基因座的基因型--包括PDGF-B链和 IGF基因座，以及PDGF-B、IGF-1、血栓素A2和PAF基因座 受体--将通过聚合酶链式反应方法进行测定。 最大似然数量遗传和复合分离分析 将被用于估计遗传力，主基因的影响，以及 多基因、主基因和候选基因的联合作用 这些性状的多态。复分离分析的推广 将被用来检测作为功能的基因类型的差异表达 协变量，例如性别和年龄。两者都是基于外显度参数的形式 将使用LOD得分分析和稳健方差分量分析来 检测与候选基因座和匿名基因座的数量性状连锁 目前正在开发的狒狒基因组图谱中的微卫星标记 为了同样的动物。拟议中的项目将增加我们的知识 关于血小板衍生生长因子正常数量变异的遗传决定因素 和相关表型，提供了有关疾病程度和性质的信息 这些表型之间的共同变异，有助于定位基因组区域 对这些性状的变异负责，并进一步建立 纯种狒狒作为动脉粥样硬化相关遗传学研究的模型。

DESCRIPTION (Adapted from the Investigator's Abstract): Platelets and platelet products, like platelet-derived growth factor (PDGF), are critical to the maintenance of hemostasis and are continually implicated in atherogenesis. However, little is understood about the genetic determination of normal quantitative variation in platelet biology. The overall objective of the proposed study is to detect the effects of genes on normal biological variation in platelet-stores of PDGF and other traits which influence its availability and activity in a nonhuman primate model for atherosclerosis. Statistical genetic methods will be used to detect and measure the effects of variation at unknown major loci, known candidate loci, anonymous microsatellite loci, and polygenes on quantitative variation in platelet stored PDGF and other PDGF-related traits. These traits, including platelet number and volume, serum platelet activating factor (PAF), plasma thromboxane B2, serum insulin- like growth factor-1 (IGF-1), and total and high density lipoprotein cholesterol, will be measured in 600 pedigreed baboons. Each animal's genotype at 6 polymorphic candidate loci -- including PDGF-B chain and IGF- loci, and the loci for the PDGF-B, IGF-1, thromboxane A2, and PAF receptors -- will be determined by polymerase chain reaction methods. Maximum-likelihood quantitative genetic and complex segregation analyses will be used to estimate heritabilities, the effects of major genes, and the joint effects of polygenes, major loci, and candidate gene polymorphisms on these traits. Extensions of complex segregation analysis will be used to detect differential expression of genotypes as functions of covariates, e.g., sex and age. Both formal penetrance-parameter-based LOD score analysis and robust variance components analysis will be used to detect quantitative trait linkage with candidate loci and the anonymous microsatellite markers from a baboon genome map currently being developed for the same animals. The proposed project will increase our knowledge about the genetic determinants of normal quantitative variation in PDGF and related phenotypes, provide information on the extent and nature of covariation among these phenotypes, help localize genomic regions responsible for variation in these traits, and further establish the pedigreed baboon as a model for atherosclerosis-related genetic research.