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.
