Modeling DNA Diversity in Reverse Cholesterol Transport
Condition: Cardiovascular Diseases; Heart Diseases; Atherosclerosis
MeSH terms: Cardiovascular Diseases; Heart Diseases; Atherosclerosis
Study type: Observational

Summary: 
      To identify genetic variation in reverse cholesterol transport (RCT) and its role in
      cardiovascular disease and atherosclerosis.
    

Detailed description: 
      BACKGROUND:

      The collaborative research project will address a major problem in genetic epidemiology,
      namely the development of strategies to rationally identify and select sites or combinations
      of sites for genotype-phenotype studies that will be most relevant for predicting and
      understanding the role of genes in physiological phenotypes. Knowledge could be advanced in
      both specific and general terms. The project will focus on the genetic architecture of 62
      genes either known or hypothesized to have a role in cholesterol transport. The data and
      conclusions generated by this project will enrich our understanding of both the extant
      genetic variation in these genes and the functional or causative relationships between such
      variation and phenotypes measured at a variety of organizational scales (pathway, systemic
      and clinical outcome). The additional focus on environmental interaction terms will enhance
      understanding of specific gene x environment interactions in the cholesterol transport
      system. The project involves three collaborating grants: R01HL72810 to Eric A. Boerwinkle at
      the University of Texas School of Public Health; R01HL72905 to Charles F. Sing at the
      University of Michigan at Ann Arbor; and R01HL72904 to Andrew Clark at Cornell University in
      Ithaca, New York.

      DESIGN NARRATIVE:

      This Collaborative Research Project will model DNA diversity in Reverse Cholesterol Transport
      (RCT) by exploring the genetic basis underlying this pathway and its contribution to
      atherosclerosis risk and cardiovascular disease (CVD). Given the progress of the Human Genome
      Project and the development of laboratory and analytic resources, the delineation of a gene's
      complete genetic architecture and contribution to individual differences within a population
      becomes (theoretically) feasible. This study will explore the variation in 8 of 62 candidate
      genes that will be screened using a battery of single nucleotide polymorphisms (SNPs). The
      eight genes (and the 6-10 SNPs within each) will be chosen based upon association with a
      surrogate quantitative trait (using a cholesterol efflux assay). The genes will be
      exhaustively characterized by analysis of DNA sequence variation, linkage disequilibrium
      (LD), and haplotypes in samples from the community-based CARDIA study. Genotype-phenotype
      relationships will be determined using analytic methods that take advantage of
      population/evolutionary history, underlying complexity, and other innovative approaches.

      Component 1 of this Collaborative Research Project under Eric Boerwinkle will generate a
      large amount of new data on complex patterns of variation in a substantial number of genes. A
      major objective is to develop methods for analyzing these data to find etiologically relevant
      aspects of variation. For each of 62 candidate genes, the initial responsibility of Component
      2 under Andrew Clark is to analyze the distribution of single DNA site and haplotype
      variation in terms of the population processes responsible for that variation. The
      investigators will develop systematic methods to identify subsets of sites that most fully
      capture the haplotypic structure of the data and thereby reduce the dimensionality of the
      variation. These methods will be applied to haplotype and genotype variation in a
      population-based sample of 2007 African-Americans and 2139 European-Americans from the CARDIA
      study. Single nucleotide polymorphisms frequency spectra, linkage disequilibrium and the
      block-wise structure of haplotypes will be quantified and related to expectations of
      population genetic theory. Novel approaches to genotype-phenotype associations will be
      pursued, in close collaboration with Component 3, by testing the fit of the neutral site
      frequency spectrum to data stratified by phenotypic measures.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        The sample to be studied by this Collaborative Research Project Grants consists of 2007
        African-Americans and 2139 European-Americans equally divided between males and females
        between 18-30 years of age at the time of entry into the Coronary Artery Risk Development
        in Young Adults (CARDIA) study in 1985.