Abstract Rationale Oxygenation impairment is a pathophysiological feature of acute respiratory distress syndrome (ARDS). Although genetic factors have been implicated in ARDS susceptibility, the genetic determinants of early oxygenation impairment as quantified by the arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2:FiO2) ratio remain unknown. Therefore, we aimed to identify single nucleotide polymorphisms (SNPs) that associate with early oxygenation impairment as a quantitative trait in sepsis-associated ARDS, hypothesizing that these loci may elucidate novel pathophysiological mechanisms. Methods We conducted a prospective cohort study of critically ill subjects with sepsis admitted to the ICU. DNA was extracted from whole blood samples. All subjects met Sepsis-3 consensus criteria. Genotype was ascertained via Affymetrix Axiom TxArrayv1 with imputation per NHLBI TOPMed reference panel. Subjects were phenotyped for ARDS by fulfilling all Berlin criteria on the same calendar day while invasively ventilated within 6 days of ICU admission. Arterial blood gases and ventilator settings were used to calculate lowest PaO2:FiO2 ratio on the date of ARDS diagnosis. We applied multivariable linear regression to test the association of genotype with PaO2:FiO2 ratio adjusting for age, sex, and genetic ancestry. A P-value of 5x10-8 was the genome-wide significance threshold. We assessed for replication of the significant loci with PaO2:FiO2 ratio in an external prospective cohort of critically ill adults genotyped via Illumina Global Screening Array adjusting for age, sex, and genetic ancestry. Results We enrolled and genotyped 815 ARDS subjects in the primary cohort. Rs11571880, a downstream variant of CCK, which encodes the cholecystokinin (CCK) peptide hormone, was associated with lowest PaO2:FiO2 at the genome-wide significance threshold (β -0.39 95%CI -0.52, -0.27, P=8.21x10-10). We identified 5 additional SNPs in linkage disequilibrium with the lead variant, which associated with lowest PaO2:FiO2 ratio (P1x10-5) (Table). We also detected a genome-wide significant association between rs74896703, in PROM1, which encodes protein prominin-1, and lowest PaO2:FiO2 ratio (β -0.62 95%CI -0.85, −0.40, P=4.57x10-8). In the external cohort (n = 185), a SNP within PROM1, rs149833181, associated with lowest PaO2:FiO2 ratio (P=0.01). Conclusion We report novel genome-wide associations between genetic variation in CCK and PROM1 and PaO2:FiO2 ratio as a quantitative trait in sepsis-associated ARDS. CCK receptors are expressed in pulmonary vascular endothelial cells and demonstrate upregulation in pulmonary interstitial macrophages in sepsis animal models. PROM1 promotes endothelial cell repair following injury. These loci warrant further replication in larger populations and mechanistic investigation to evaluate their therapeutic potential in ARDS. This abstract is funded by: HL149851 (T.K.J.), RWJF 127279 (T.K.J), HL161196 (N.J.M.)
Jones et al. (Fri,) studied this question.