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Genetic Variation in MAP3K1 Associates with Ventilator-free Days in Acute Respiratory Distress Syndrome

Morrell, ED;O'Mahony, DS;Glavan, BJ;Harju-Baker, S;Nguyen, C;Gunderson, S;Abrahamson, A;Radella Ii, F;Rona, G;Black, RA;Wurfel, MM;

Mitogen activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with acute respiratory distress syndrome (ARDS), and that these variants would alter MAP3K1-mediated changes in inflammation and transcriptional regulation. To test this hypothesis, we genotyped single nucleotide polymorphisms (SNPs) covering linkage disequilibrium bins in MAP3K1 in 306 subjects with ARDS from the ARDSNet FACTT study, and tested for associations between MAP3K1 SNPs and ventilator-free days (VFD) and mortality. We then validated these associations in a separate cohort of 241 patients with ARDS from Harborview Medical Center (HMC). We found the variant allele of rs832582 (MAP3K1906Val) was significantly associated with decreased VFDs using multivariate linear regression (-6.1 days, false discovery rate (FDR)=0.06) in the FACTT cohort. In the HMC cohort, subjects homozygous for MAP3K1906Val also had decreased VFDs (-15.1 days, FDR<0.01), and increased 28-day mortality (all subjects homozygous for the rare allele died). In whole blood stimulated with various innate immune agonists ex vivo, MAP3K1906Val was associated with increased IL-1, IL-6, IL-8, monocyte chemoattractant protein (MCP-1), and tumor necrosis factor alpha (TNF-) production. Transcriptome analysis of whole blood stimulated with TLR4 agonist ex vivo demonstrated enrichment of inflammatory gene sets in subjects homozygous for MAP3K1906Val. Our findings show a robust association between the variant allele of rs832582 (MAP3K1906Val) and decreased VFDs in patients with ARDS, and suggest that this variant may predispose individuals towards a greater inflammatory response.