• Christian Bime, Nima Pouladi, Saad Sammani, Ken Batai, Nancy Casanova, Tong Zhou, Carrie L Kempf, Xiaoguang Sun, Sara M Camp, Ting Wang, Rick A Kittles, Yves A Lussier, Tiffanie K Jones, John P Reilly, Nuala J Meyer, Jason D Christie, Jason H Karnes, Manuel Gonzalez-Garay, David C Christiani, Charles R Yates, Mark M Wurfel, Gianfranco U Meduri, and GarciaJoe G NJGN1 Department of Medicine..
• 1 Department of Medicine.
• Am. J. Respir. Crit. Care Med. 2018 Jun 1; 197 (11): 142114321421-1432.

RationaleGenetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches.ObjectivesTo identify genetic susceptibility targets for ARDS.MethodsA genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort.Measurements And Main ResultsPathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg-/- mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation.ConclusionsThese findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.

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