BACKGROUND Innate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients.METHODS We assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multicenter Lung Transplant Outcomes Group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed.RESULTS Y238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in bronchoalveolar lavage (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared with wild-type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0–1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0–2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1–3.8) and in the LTOG cohort (HR 1.3, CI 1.1–1.6), compared with wild-type CLEC7A subjects.CONCLUSION Increased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition.FUNDING The UCSF Nina Ireland Program for Lung Health Innovative Grant program, the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.
Daniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, John R. Greenland
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