Platelets are thought to be critical in pulmonary-origin acute respiratory distress syndrome (ARDS) as mediators of endothelial damage through their interactions with fibrinogen and multiple signal transduction pathways. A prior meta-analysis identified 5 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.
ARDS cases and at-risk controls 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 controls, and genome-wide gene expression profiles of 18 at-risk controls were generated for analysis.
Single-nucleotide polymorphism (SNP) rs7766874 within LRRC16A was a significant locus for PLT among at-risk controls [β =-13.00, 95% confidence interval (95%CI) =-23.22∼-2.77, p =0.013]. This association was validated using LRRC16A gene expression data from at-risk controls (β =77.03 per 1 standard-deviation increase of log2-transformed expression, 95%CI =27.26∼126.80, p =0.005). Further, rs7766874 was associated with ARDS risk conditioned on PLT [odds ratio (OR) =0.68, 95%CI =0.51∼0.90, p =0.007], interacting with PLT (OR =1.15 per effect allele per 100×103/µL of PLT, 95%CI =1.03∼1.30, p =0.015), and mediated through PLT (ORIndirect =1.045, 95%CI =1.007∼1.085, p =0.021).
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, platelet.