Electronic health record biobank cohort recapitulates an association between the MUC5B promoter polymorphism and ARDS in critically ill adults.

BackgroundLarge population-based DNA biobanks linked to electronic health records (EHRs) may provide novel opportunities to identify genetic drivers of ARDS. Research QuestionCan we develop an EHR-based algorithm to identify ARDS in a biobank database, and can this validate a previously reported ARDS genetic risk factor? Study Design and MethodsWe analyzed two parallel genotyped cohorts: a prospective biomarker cohort of critically ill adults (VALID), and a retrospective cohort of hospitalized participants enrolled in a de-identified EHR biobank (BioVU). ARDS was identified by clinician-investigator review in VALID and an EHR algorithm in BioVU (EHR-ARDS). We tested the association between the MUC5B promoter polymorphism rs35705950 with development of ARDS, and assessed if age modified this genetic association in each cohort. ResultsIn VALID, 2,795 patients were included, age was 55 [43, 66] (median [IQR]) years, and 718 (25.7%) developed ARDS. In BioVU, 9,025 hospitalized participants were included, age was 60 [48, 70] years, and 1,056 (11.7%) developed EHR-ARDS. We observed a significant age-related interaction effect on ARDS in VALID: among older patients, rs35705950 was associated with increased ARDS risk (OR: 1.44; 95%CI 1.08-1.92; p=0.012) whereas among younger patients this effect was absent (OR: 0.84; 95%CI: 0.62-1.14; p=0.26). In BioVU, rs35705950 was associated with increased risk for EHR-ARDS among all participants (OR: 1.20; 95%CI: 1.00-1.43, p=0.043) and this did not vary by age. The polymorphism was also associated worse oxygenation in mechanically ventilated BioVU participants, but had no association with oxygenation in VALID. InterpretationThe MUC5B promoter polymorphism was associated with ARDS in two cohorts of at-risk adults. Although age-related effect modification was observed only in VALID, BioVU identified a consistent association between MUC5B and ARDS risk regardless of age, and a novel association with oxygenation impairment. Our study highlights the potential for EHR biobanks to enable precision-medicine ARDS studies.