An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is an increasingly recognized, often fatal lung disease of unknown etiology. OBJECTIVES: The aim of this study was to use whole-exome sequencing to improve understanding of the genetic architecture of pulmonary fibrosis. METHODS: We performed a case-control exome-wide collapsing analysis including 262 unrelated individuals with pulmonary fibrosis clinically classified as IPF according to American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines (81.3%), usual interstitial pneumonia secondary to autoimmune conditions (11.5%), or fibrosing nonspecific interstitial pneumonia (7.2%). The majority (87%) of case subjects reported no family history of pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: We searched 18,668 protein-coding genes for an excess of rare deleterious genetic variation using whole-exome sequence data from 262 case subjects with pulmonary fibrosis and 4,141 control subjects drawn from among a set of individuals of European ancestry. Comparing genetic variation across 18,668 protein-coding genes, we found a study-wide significant (P < 4.5 × 10-7) case enrichment of qualifying variants in TERT, RTEL1, and PARN. A model qualifying ultrarare, deleterious, nonsynonymous variants implicated TERT and RTEL1, and a model specifically qualifying loss-of-function variants implicated RTEL1 and PARN. A subanalysis of 186 case subjects with sporadic IPF confirmed TERT, RTEL1, and PARN as study-wide significant contributors to sporadic IPF. Collectively, 11.3% of case subjects with sporadic IPF carried a qualifying variant in one of these three genes compared with the 0.3% carrier rate observed among control subjects (odds ratio, 47.7; 95% confidence interval, 21.5-111.6; P = 5.5 × 10-22). CONCLUSIONS: We identified TERT, RTEL1, and PARN-three telomere-related genes previously implicated in familial pulmonary fibrosis-as significant contributors to sporadic IPF. These results support the idea that telomere dysfunction is involved in IPF pathogenesis.

Lung transplantation at Duke University.

Clinical lung transplantation continues to grow worldwide. Advances in donor selection and management have been critical to support the expanded growth of lung transplant as a therapeutic option for patients with advanced lung disease. In recent years, allocation in the US has changed to a disease severity based system that has led to a dramatic reduction of deaths on the waiting list with concomitant increases in transplantation of recipients who are now sicker, older, and more likely to have interstitial lung disease. Increased experience with the LAS will help to further refine optimal recipient selection and balance urgency with utility. Our center's experience demonstrates survival is comparable post-LAS as compared to pre-LAS despite transplantation of increasingly ill recipients. After transplantation, the incidence of severe PGD has decreased in recent years with advances in donor lung management and perseveration. In cases of severe PGD, VV ECMO has provided our center with a successful method of supporting patients and reducing mortality immediately following transplantation. Long-term outcomes after lung transplantation continue to be limited by BOS, a condition of progressive allograft dysfunction. Our center has led research that identified gastric reflux as a potential contributing factor to posttransplant allograft dysfunction and suggested that Nissen fundoplication surgery might help prevent the development of BOS. Continued refinements in donor management and selection, prevention and treatment of PGD, and enhanced understanding of the mechanisms of BOS will support further growth of lung transplantation and further improvements in overall posttransplant outcomes.

Lung transplantation at Duke University Medical Center.

Lung transplantation has undergone remarkable changes in clinical practice to address the higher rate of rejection and mortality. Our protocols include increased immunosuppression and strategies to address non-alloimmune injury, including GER. New and innovative approaches to lung transplantation are still needed to improve short- and long-term outcomes. The LAS implementation has had a strong influence on the type of native disease transplanted at our center as well as our waiting list time. However, the LAS was not predictive of survival posttransplant at one year. Further refinements of the LAS and protocols may improve survival posttransplant.