Elucidating the genomic determinants of outcomes in idiopathic pulmonary fibrosis

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PROJECT SUMMARY/ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a rare, but devastating interstitial lung disease characterized by a progressive decline in lung function and a median survival of 3-5 years after diagnosis. Despite the poor prognosis, IPF follows a highly variable clinical course, whereby most patients experience gradual disease progression, some demonstrate relative stability and a small group dies from rapidly progressive disease. Anti- fibrotic therapies were recently approved for the treatment of IPF, but it remains unclear which IPF phenotypes derive the most benefit. Recent advances in genomic technology provide an excellent opportunity to improve our understanding of IPF progression and treatment response. In this proposal, I aim to take advantage of these genomic advances to identify single nucleotide polymorphisms (SNPs) linked to relevant IPF outcomes. I will do this using DNA samples collected from patients enrolled in past and current IPF clinical trials, along with two large IPF registries. My central hypothesis is that patients genetically predisposed to death, disease progression and treatment response can be prospectively identified using SNPs linked to these endpoints. I will first conduct a genome-wide survival analysis to identify SNPs linked to early IPF mortality. I will then genotype relevant susceptibility and outcome-associated SNPs in several clinical trial datasets to determine whether they predict relevant trial endpoints, including pulmonary function decline and hospitalization. Finally, I will genotype SNPs at potential pharmacogenetic loci to determine whether such SNPs modulate the response to anti-fibrotic therapy. Successful completion of this proposal will lead to the development of customized SNP chips that inform the design of IPF clinical trials and has a high potential to identify novel genes that may one day serve as therapeutic targets. My long-term career goal is to incorporate genetics into clinical decision-making in patients with IPF, specifically clinical trial enrollment and therapeutic selection. To make progress towards this goal, the relevant genetic markers with which to stratify IPF cohorts for risk-stratification and pharmacogenetic testing must first be identified. To do this, a career development has been devised that will provide outstanding mentorship, hands-on laboratory experience and additional training in genetic epidemiology, statistical genetics and bioinformatics. I will draw mentorship from leaders in the field of genomics, interstitial lung disease and clinical and translational investigation. An advisory committee composed of individuals with diverse backgrounds has been assembled to provide specific guidance with regard to clinical registry and biorepository management, laboratory training, statistical genetics and outcomes modeling. This K23 award is vital to successful completion of this proposal and timely execution of my career development plan, as it will provide the time necessary to meet the realistic milestones that have set in conjunction with my advisory committee. Ultimately this award will allow me to successfully compete for R01 funding aimed at advancing my long-term goal above. The research environment at UC Davis is among the best in the country and includes the NIH-funded Clinical and Translational Science Center (CTSC), the Career Development Core funded by the NIEHS P30 program in Environmental Health Sciences (ESH), the Center for Comparative Respiratory Biology and Medicine (CCRBM) and the Integrative Genetics and Genomics Graduate Group (IGG). The UC Davis CTSC was one of the original 12 NIH-supported Centers nationally and provides resources in bioinformatics, IRB submission and the conduct of investigator-initiated clinical trials. The EHS career development core provides vital assistance to junior investigators launching research careers including mentorship workshops, grant writing assistance and laboratory leadership-focused seminars. The CCRBM, which includes many collaborative investigators focused on pulmonary fibrosis, also offers graduate classes in clinical and advanced biostatistics. The IGG provides additional coursework in genetic epidemiology, statistical genetics and bioinformatics. Coupled with a large and well-established ILD program, UC-Davis has an established track record of excellence in patient- oriented research and provides the ideal environment in which to conduct this proposal. !