Lung Transplant Recipients Carrying rs2241880 GG Genotype of the Autophagy Gene ATG16L1 Are at Accelerated Risk for BOS Development

Purpose: Autophagy is a catabolic process that promotes cytoplasmic component cycling and is implicated in regulating alloimmune responses by dendritic cells. Carriers of autophagy gene ATG16L1 (rs2241880, T300A) G alleles are at increased risk for Crohn’s disease but the role of this genotype in solid organ transplant tolerance is unclear. Here we assess BOS development risk in lung transplant recipients at rs2241880. Methods: A retrospective chart review of 230 recipients who received lungs between 12/1/09 and 10/31/13 was performed. Donor and recipient demographic data were extracted along with time to first occurrence of post-transplant Grampositive (inc. S. aureus and other), Gram-negative (inc. P aeruginosa and other), Aspergillus (inc. A. fumigatus, A. niger, A. flavus, or other), cytomegalovirus (CMV) and respiratory viral infection (inc. influenza, respiratory syncytial virus, adenovirus, and other). Recipient saliva DNA samples were collected from 239 recipients. Results: ATG16L1 rs2241880 polymorphisms could be determined from 229 participants. 60 recipients were AA, 101 AG, and 68 GG. Univariate analysis revealed statistically significant differences in BOS development rates between AA, AG and GG (p ≤ 0.0016). This result remained statistically significant when multivariate analysis was applied to infections (as indicated in the methods) as covariates (p= 0.008) for AA vs. GG but not AG vs. AA or GG. Conclusion: Carriers of ATG16L rs2241880 GG are prone to faster BOS development suggesting that the underlying immune mechanisms that promote chronic rejection are regulated by autophagy. of Respiratory Medicine, Alfred Hospital, Melbourne, Australia; 4Division of Respiratory Medicine, Lausanne University Hospital, Lausanne, Switzerland; 5Division of Respiratory Medicine, Basel University Hospital, Basel, Switzerland; 6Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA; 7Division of Cardiothoracic Surgery, University of California, San Francisco Medical Center, San Francisco, CA.