Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition that arises from multiple causes, including sepsis, pneumonia, trauma, and severe coronavirus disease 2019 (COVID-19). Given the heterogeneity of causes and the lack of specific therapeutic options, it is crucial to understand the genetic and molecular mechanisms that underlie this condition. The identification of genetic risks and pharmacogenetic loci, which are involved in determining drug responses, could help enhance early patient diagnosis, assist in risk stratification of patients, and reveal novel targets for pharmacological interventions, including possibilities for drug repositioning. Here, we highlight the basis and importance of the most common genetic approaches to understanding the pathogenesis of ARDS and its critical triggers. We summarize the findings of screening common genetic variation via genome-wide association studies and analyses based on other approaches, such as polygenic risk scores, multi-trait analyses, or Mendelian randomization studies. We also provide an overview of results from rare genetic variation studies using Next-Generation Sequencing techniques and their links with inborn errors of immunity. Lastly, we discuss the genetic overlap between severe COVID-19 and ARDS by other causes.

Introduction: Acute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted the largest genome-wide association study (GWAS) of sepsis-associated ARDS to identify novel genetic risk loci that can help guide the development of new therapeutic options. Methods: We performed a case-control GWAS in 716 patients with sepsis-associated ARDS and 4,399 at-risk sepsis controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p <5×10 ^-8 . Suggestive associations were declared for variants exhibiting consistent effects, likely to replicate and nominal significance ( p <0.05) in all three studies. Prioritised loci were subjected to Bayesian fine mapping, in-silico functional assessments, and gene-based rare variant collapsing analysis using whole exome sequencing (WES) data. Two independent studies with 430 ARDS cases and 1,398 controls served as replication samples. Results: We identified a variant showing genome-wide significant association with sepsis-associated ARDS risk intergenic to ANKRD31 and HMGCR , previously linked to cholesterol metabolism. Suggestive associations were found for eight other variants. The rare exonic variant analysis showed associations between HMGCR and POC5 and sepsis-associated ARDS at nominal level ( p <0.05). While no nominal significance was achieved in the two additional validation cohorts, three variants exhibited a consistent direction of effects across all 5 studies. Conclusion: A common variant intergenic to ANKRD31 and HMGCR was associated with sepsis-associated ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.

Background: Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition that requires admission to an intensive care unit (ICU). Sepsis is one of the leading causes of ARDS and understanding protein regulation during sepsis could reveal key mechanisms that predispose patients to ARDS. We performed genome-wide association studies (GWAS) on ARDS biomarkers levels to identify protein quantitative trait loci (pQTLs) and genes which could be associated with ARDS risk. Methods: GWAS were performed in 209 patients with sepsis from the GEN-SEP cohort to determine the association of imputed genotypes with 10 serum biomarker levels relevant to ARDS. Measurements were obtained by ELISA within the first 24 hours (T1), 48-72 hours (T2), and 7 days (T7) after the diagnosis of sepsis. We conducted a multi-trait analysis to aggregate the GWAS results for each biomarker at three time points. We prioritized genes in the significant loci (p<5x10 ^-8 ) and evaluated the association between rare variants and ARDS in whole-exome sequencing data from 272 patients with sepsis-associated ARDS and 550 sepsis controls from GEN-SEP. We analyzed the aggregated association of pQTLs with ICU mortality, multiple organ failure, and ARDS risk using polygenic scores (PGS) in independent patients (n=621) from GEN-SEP. Results: We identified 27 significant independent loci and prioritized 56 genes. Seven of these were previously associated with respiratory infections and diseases ( LINGO2 , MC4R , MCTP1 , NUAK1 , PIEZO2 , PTPRD , and TMEM65 ). Defects in another prioritized gene, FOXN1 , cause an inborn error of immunity. Rare variants in PTPRD , which was previously involved in COVID-19 severity and pulmonary hypertension, were significantly associated with ARDS (p=3.11x10 ^-4 ). PGS of PAI-1 levels was significantly associated with ICU mortality. Conclusions: We prioritized genes of interest governing ARDS biomarker levels and identified PTPRD as a novel gene associated with ARDS risk. In addition, we demonstrate the value of biomarker PGS for predicting sepsis mortality.