title: Platelet count mediates the contribution of a genetic variant in LRRC16A to ARDS risk.
abstract: 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 log2-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 × 103/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.
authors.affiliation: Department of Environmental Health, Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA.
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA.
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA.
authors.forename: Paula
authors.initials: P
authors.lastname: Tejera
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors.forename: Ednan K
authors.initials: EK
authors.lastname: Bajwa
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Washington, Harborview Medical Center, Seattle, WA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Wurfel
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA.
authors.forename: Xihong
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Environmental Health, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: dchris@hsph.harvard.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D016638:Critical Illness; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D010976:Platelet Count; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000097:blood* / Q000235:genetics* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: C547525:CARMIL1 protein, human; D008840:Microfilament Proteins