Bronchiolitis obliterans syndrome (BOS), a clinical syndrome of irreversible, progressive airway disease causing obstructive lung disease (OLD), is a serious complication of hematopoietic stem cell transplant (HSCT). Research investigating the pathogenesis of BOS suggests that this form of OLD is immune mediated and consistent with pulmonary graft versus host disease (GVHD). Since proinflammatory and anti-inflammatory cytokines play a significant role in the pathophysiology of GVHD and the production of these cytokines is influenced by environmental and genetic factors, we believe there are genetic determinants other than histocompatibility disparity that influence the risk of developing OLD after HSCT. This project will develop a new collaborative effort between investigators in lung medicine and immunology and genetic epidemiologists to utilize an existing source of stored DNA and a novel haplotypic approach in exploring the hypothesis that allelic haplotypes of genes in the lipopoly-saccharide (LPS) inflammatory pathway influence the risk of developing OLD after HSCT.
Aim 1 will assess for the association of susceptibility as well as protective allelic haplotypes of genes in the LPS inflammatory pathway in both diseased as well as hypernormal individuals. The allelic haplotypes will be generated using the Phase program developed at the University of Washington. These haplotypes are generated by selecting for single nucleotide polymorphisms (SNPs) with an allele frequency ?10% that exist in significant linkage disequilibrium with each other. When multiple such haplotypes are considered for each gene, a nonbiased analysis of nearly the entire gene can be performed for association with a complex disease.
Aim 2 will confirm the association and linkage of certain allelic haplotypes of the genes in the LPS inflammatory pathway with OLD using an established family-based study design, the transmission disequilibrium test. Father, mother, and proband offspring trios will be identified in our DNA resource for genotyping to determine if haplotypes found to be significantly associated with OLD in aim 1 are indeed genetically linked and associated with disease in a family based analysis. Use of allelic haplotypes will provide an unbiased look for association with disease throughout the entire gene and an opportunity to perform rigorous fine genetic mapping and gene discovery. Ultimately, this insight can be applied to understand inflammation and how it causes more common lung diseases.
