Cystic fibrosis (CF) is a recessive "monogenic" genetic disorder, but there is great variability in pulmonary disease severity and survival, even among patients who are homozygous for deltaF508. We hypothesize that much of the variability of CF lung disease reflects the influence of relatively common non-CFTR genetic polymorphisms. We have developed a multi-center gene modifier study that focuses on testing genetic variation in CF patients at the extremes of pulmonary phenotype, i.e., "severe" versus "mild" lung disease (worst or best 25th percentile for age). Recent studies in these patients provide strong support for the role of modifier genes in severity of disease. Genetic variation in TGFbeta1 strongly associates with severity of lung disease (p=5.9 x e-8 for 1306 patients), and the relative risk is high (OR approximately 2.2) for contribution of a gene modifier to a Mendelian disorder. We will use this population of well-defined patients to continue our ongoing study of genetic modifiers in CF. First, we will continue to pursue studies of candidate genes in key pathophysiological pathways and in genes that are not amenable to current high throughput genotyping methodologies, such as HLA and respiratory mucin genes. Second, to identify new candidate loci and genes, we will perform a whole genome scan at high resolution (250-500,000 SNPs). The whole genome scan will be performed using a two-stage approach. In the first stage, we will use the whole genome scan to genotype 500 deltaF508 homozygotes (250 severe and 250 mild). In the second stage, we will genotype approximately 10,000 of the most significant SNPs from the first stage in 900 additional CF patients (70% deltaF508 homozygotes). This two-stage approach is nearly as robust as genotyping all subjects for 250-500,000 SNPs, but much less expensive. Finally, we will follow up significant SNPs that emerge from the whole genome studies, using computational and genetic approaches to more precisely define the genetic variants. Our overall goal is to identify most of the major gene modifiers in CF, which will 1) greatly improve prognostic capabilities;2) define key pathobiological pathways that have genetic variation of clinical importance;and 3) identify new therapeutic targets. If successful, this study will offer unprecedented opportunities for novel prognostic and therapeutic approaches in CF. It will also likely provide insight into genetic pathophysiology of more common lung diseases, such as asthma and chronic obstructive pulmonary disease. The relevance of this project is that identification of genes altering the disease outcome in CF will provide us with new targets for therapy. Natural variation in the disease proves that there must be ways to alter its course, and this project has the power to identify genetic sources of that variation.