Wei Yongyue, Wang Zhaoxi, Su Li, Chen Feng, Tejera Paula, Bajwa Ednan K, Wurfel Mark M, Lin Xihong, Christiani David C
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.
Department of Environmental Health, Harvard School of Public Health, Boston, MA.
Chest. 2015 Mar;147(3):607-617. doi: 10.1378/chest.14-1246.
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.
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.
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).
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.
血小板被认为在肺源性急性呼吸窘迫综合征（ARDS）中起关键作用，它通过与纤维蛋白原及多种信号转导途径相互作用，成为内皮损伤的介质。一项先前的荟萃分析确定了五个血小板计数（PLT）相关基因座：BAD、LRRC16A、CD36、JMJD1C和SLMO2。本研究旨在验证危重症患者中BAD、LRRC16A、CD36、JMJD1C和SLMO2内PLT的数量性状基因座（QTL），并研究这些QTL与可能通过PLT介导的ARDS风险之间的关联。
从马萨诸塞州总医院重症监护病房招募ARDS病例和高危对照受试者。生成629例ARDS病例和1026例高危对照受试者的外显子组全基因分型数据以及18例高危对照受试者的全基因组基因表达谱用于分析。
LRRC16A内的单核苷酸多态性（SNP）rs7766874是高危对照受试者中PLT的一个显著基因座（β = -13.00；95%置信区间，-23.22至-2.77；P = 0.013）。使用高危对照受试者的LRRC16A基因表达数据验证了这种关联（每log2转换表达增加1个标准差，β = 77.03；95%置信区间，27.26 - 126.80；P = 0.005）。此外，rs7766874与以PLT为条件的ARDS风险相关（比值比[OR] = 0.68；95%置信区间，0.51 - 0.90；P = 0.007），与PLT相互作用（每100×10³/μL PLT的每个效应等位基因，OR = 1.15；95%置信区间，1.03 - 1.30；P = 0.015），并通过PLT介导（间接OR = 1.045；95%置信区间，1.007 - 1.085；P = 0.021）。
我们的研究结果支持LRRC16A在血小板形成中的作用，并表明LRRC16A通过与血小板相互作用并由血小板介导，在ARDS病理生理学中具有重要意义。
