Rationale:  Acute respiratory distress syndrome (ARDS) risk is incompletely explained by clinical factors. Prior studies have identified genetic risk factors for ARDS primarily in European ancestry (EA) populations without testing associations in African ancestry (AA). We conducted a genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with sepsis-associated ARDS in a diverse population, testing EA loci for replication in AA subjects.

Methods: We enrolled 1,733 critically ill patients with sepsis and extracted DNA from whole blood. Genotype was ascertained by Affymetrix Axiom TxArrayv1. ARDS was phenotyped by Berlin criteria.  We applied multivariable logistic regression to test the association of genotype with ARDS risk adjusting for age, sex, and genetic ancestry. We used the larger EA population for discovery and AA as the replication population. A p-value of 5x10-8 was considered the genome-wide significance threshold, and a p-value of 1x10-5 was considered the nominal threshold based on the anticipated power. 

Results:  We genotyped 1,135 (65%) EA and 597 (35%) AA subjects. ARDS developed in 624 (36%).  No SNP met the traditional GWAS significance threshold, but 4 EA and 3 AA variants achieved nominal significance.  In EA, rs12934553 within WWOX, which encodes tumor suppressor WW domain-containing oxidoreductase, was highly associated with ARDS risk (OR 0.66 [95%CI 0.56 – 0.79], p=3.71 x 10-6). This association was replicated in AA with opposite directionality (OR 1.76 [95%CI 1.20– 2.60], p=3.71 x 10-6). Two other loci within WWOX were nominally associated with ARDS risk in both EA and AA. In addition, rs2592293 in KSR2, a kinase suppressor of Ras 2, was associated with ARDS risk (EA OR 2.88 [95%CI 1.85 – 4.51], p=3.01 x 10-6); AA OR 4.83 [95%CI 1.25 – 18.64], p=0.02).  

Conclusion:  We demonstrate both shared and unique genetic risk factors for sepsis-associated ARDS by ancestry.  Although no variant achieved conventional GWAS significance, multiple variants surpassed a nominal threshold suggesting polygenic architecture. Several loci replicated across ancestries. WWOX has been implicated in neutrophilic lung injury, tobacco exposure, and vascular permeability. Co-localizing signals with opposing directionality may occur due to different genetic population structure, epigenetic changes, or interacting factors. As a scaffold protein regulating ERK signaling, KSR2 is another compelling ARDS candidate gene. Both findings warrant further investigation and replication. Increased diversity in genetic studies may enhance our potential for elucidation of ARDS pathobiology.