FUNCTIONAL GENOMICS CENTER FOR INNATE IMMUNITY PGA

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PROPOSED PROGRAM (Adapted from the Applicant's Abstract) Asthma, chronic obstructive pulmonary disease (COPD), myocardial infarction (MI), and deep venous thrombosis (DVT) are among the most common diseases of the lung, heart, and blood (ref). The combined health care costs for these conditions approximate 100 billion dollars per year. The goal of the RFA HL- 99-024 Genomic Applications for Heart, Lung, and Blood Research is to develop and expand genomic knowledge within the heart, lung, and blood community and apply that knowledge to disease pathobiology. There have been considerable advances in the understanding of the disease mechanisms for these conditions, and all four are associated with the development of a local inflammatory process. It has become apparent that cells and cytokines that are part of the innate immune system control the early phases of this process of airway, lung, and blood vessel inflammation. The proposal builds on the strengths of three institutions: the Respiratory Sciences Center at the University of Arizona (UA), the Department of Medicine at Brigham & Women's Hospital (BWH), and the Bioinformatics Program at Children's Hospital in Boston (CH), to develop a human variation discovery program on the theme of non-cognate immunity and its broad relationship to heart, lung, and blood diseases. The Arizona/BWH PGA will provide the scientific community with a complete screen of the genetic variants in a subset of innate immunity genes that are most likely to influence the risk for the four diseases noted above. The investigators will also perform a preliminary assessment of the association of these variants with the four phenotypes under study, to guide researchers in these areas away from variants with low likelihood of being relevant and toward those showing promising functional and epidemiologic evidence of influencing any of the four disease phenotypes. To accomplish this broad goal, the investigators have the following specific aims: (1) To screen for polymorphisms 100 genes known to be directly or indirectly related to the innate immune response; (2) To genotype a sample of individuals of Hispanic, non-Hispanic White, and African American ethnicity for all the newly discovered polymorphisms; (3) To perform association studies and phylogenetic analysis to identify SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction, and deep venous thrombosis; (4) To disseminate the information on ethnic-specific and phenotype-specific distribution of the polymorphisms under study on a web site within 60 days of the completion of the genotyping studies; (5) To develop a training program that will allow individuals with different knowledge and experience to become acquainted with modern genetic techniques in the fields of high throughput sequencing and genotyping; study design, data handling and data analysis in genetic epidemiology; and ethical issues in population genetics.