Platelet Count Mediates the Contribution of a Genetic Variant in LRRC16A to ARDS Risk

BACKGROUND Platelets are believed to be critical in pulmonary-origin ARDS as mediators of endothelial damage through their interactions with fibrinogen and multiple signal transduction pathways. A prior meta-analysis identified five loci for platelet count (PLT): BAD , LRRC16A , CD36 , JMJD1C , and SLMO2 . This study aims to validate the quantitative trait loci (QTLs) of PLT within BAD , LRRC16A , CD36 , JMJD1C , and SLMO2 among critically ill patients and to investigate the associations of these QTLs with ARDS risk that may be mediated through PLT. METHODS ARDS cases and at-risk control subjects were recruited from the intensive care unit of the Massachusetts General Hospital. Exome-wide genotyping data of 629 ARDS cases and 1,026 at-risk control subjects and genome-wide gene expression profiles of 18 at-risk control subjects were generated for analysis. RESULTS Single-nucleotide polymorphism (SNP) rs7766874 within LRRC16A was a significant locus for PLT among at-risk control subjects (β = −13.00; 95% CI, −23.22 to −2.77; P = .013). This association was validated using LRRC16A gene expression data from at-risk control subjects (β = 77.03 per 1 SD increase of log 2 -transformed expression; 95% CI, 27.26-126.80; P = .005). Further, rs7766874 was associated with ARDS risk conditioned on PLT (OR = 0.68; 95% CI, 0.51-0.90; P = .007), interacting with PLT (OR = 1.15 per effect allele per 100 × 10 3 /μL of PLT; 95% CI, 1.03-1.30; P = .015), and mediated through PLT (indirect OR=1.045; 95% CI, 1.007-1.085; P = .021). CONCLUSIONS Our findings support the role of LRRC16A in platelet formation and suggest the importance of LRRC16A in ARDS pathophysiology by interacting with, and being mediated through, platelets.