Static Compliance of the Respiratory System is a Genetically Regulated Quantitative Trait in Sepsis-Associated Acute Hypoxemic Respiratory Failure

Abstract Rationale: Static compliance of the respiratory system (Crs) is an objective measurement of lung and chest wall stiffness and a relevant quantitative trait in acute hypoxemic respiratory failure (AHRF). Genetic polymorphisms associated with Crs in AHRF may elucidate pathophysiology and identify important targets for treatment and prevention. We aimed to identify single-nucleotide polymorphisms (SNPs) associated with Crs in a cohort of patients with sepsis and AHRF requiring mechanical ventilation (MV), and to determine their relationship with 30-day mortality. Methods: We conducted a genome-wide association study of Crs on the day of MV initiation in a prospective cohort of patients admitted to the intensive care unit with sepsis from 2011-19. We included cohort participants newly requiring MV within 48 hours after ICU admission. We determined genotype using the Affymetrix Axiom TxArrayv1 with DNA extracted from whole blood. The outcome was average Crs on the first day of MV, collected every 8 hours by clinical respiratory therapists. We used multivariable linear regression to test the association of genotype with Crs, adjusted for genetic ancestry by principal components, age, and sex, assuming additive genetic effects. We considered p<5x10-8 to have genome-wide significance and p<1x10-6 to be suggestive. We excluded SNPs with a minor allele frequency of less than 5%. We examined the relationship between compliance-associated variants and 30-day mortality with logistic regression adjusted for principal components. Results: Of 691 participants, the median (interquartile range) Crs was 32.3 mL/cmH2O (23.3-40.0). 30-day mortality was high at 60%. One intergenic SNP (rs41409444) between LINC02484 and ARAP2 met genome-wide significance for association with higher compliance (p = 5.40 x 10-9); this SNP was also associated with decreased mortality (odds ratio 0.65, 95% CI 0.46 – 0.93). Several other SNPs that met suggestive criteria for Crs were also associated with decreased mortality (Table), including an intronic SNP on the SLC40A1 gene, an intergenic SNP near LINC01310, and five additional SNPs between LINC02484 and ARAP2. Conclusion: We report several polymorphisms associated with increased Crs and decreased mortality in AHRF. ARAP2, LINC02484, and LINC01310 have been implicated in the genetic regulation of obesity and the metabolic syndrome, and their association with compliance and mortality may reflect biologic pathways by which adiposity confers a protective effect in critical illness. Additionally, SCL40A1 encodes ferroportin, an iron transport protein important in mitigating pulmonary fibrosis via regulation of fibroblast iron accumulation. These genes warrant further investigation as potential mechanisms and targets in AHRF pathophysiology.