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Original Research: Critical Care |

Platelet Count Mediates the Contribution of a Genetic Variant in LRRC16A to ARDS RiskLRRC16A Genetic Variant, Platelet Count, and ARDS

Yongyue Wei, PhD; Zhaoxi Wang, PhD; Li Su, BSc; Feng Chen, PhD; Paula Tejera, PhD; Ednan K. Bajwa, MD; Mark M. Wurfel, MD, PhD; Xihong Lin, PhD; David C. Christiani, MD, FCCP
Author and Funding Information

From the Department of Environmental Health (Drs Wei, Wang, Tejera, and Christiani and Ms Su) and Department of Biostatistics (Dr Lin), Harvard School of Public Health, Boston, MA; Department of Medicine (Drs Bajwa and Christiani), Massachusetts General Hospital, Harvard Medical School, Boston, MA; Division of Pulmonary and Critical Care Medicine (Dr Wurfel), University of Washington, Harborview Medical Center, Seattle, WA; and Department of Epidemiology and Biostatistics (Drs Wei and Chen), Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China.

CORRESPONDENCE TO: David C. Christiani, MD, FCCP, Bldg I, Room 1401, 665 Huntington Ave, Boston, MA 02115; e-mail: dchris@hsph.harvard.edu


FOR EDITORIAL COMMENT SEE PAGE 585

FUNDING/SUPPORT: This work was supported by the National Heart, Lung, and Blood Institute [Grant R01HL060710 to Dr Christiani], the National Natural Science Foundation of China [Grant 81402764 to Dr Wei, Grant 81473070 to Dr Chen], and the Natural Science Foundation of Jiangsu, China [Grant BK20140907 to Dr Wei].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(3):607-617. doi:10.1378/chest.14-1246
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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.

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