Wei Yongyue, Tejera Paula, Wang Zhaoxi, Zhang Ruyang, Chen Feng, Su Li, Lin Xihong, Bajwa Ednan K, Thompson B Taylor, Christiani David C
1 Department of Environmental Health and.
2 Department of Biostatistics, School of Public Health and.
Am J Respir Crit Care Med. 2017 May 15;195(10):1353-1361. doi: 10.1164/rccm.201605-0946OC.
Platelets are believed to contribute to acute respiratory distress syndrome (ARDS) pathogenesis through inflammatory coagulation pathways. We recently reported that leucine-rich repeat-containing 16A (LRRC16A) modulates baseline platelet counts to mediate ARDS risk.
To examine the role of LRRC16A in ARDS survival and its mediating effect through platelets.
A total of 414 cases with ARDS from intensive care units (ICUs) were recruited who had exome-wide genotyping data, detailed platelet counts, and follow-up data during ICU hospitalization. Association of LRRC16A single-nucleotide polymorphisms (SNPs) and ARDS prognosis, and the mediating effect of SNPs through platelet counts were analyzed. LRRC16A mRNA expression levels for 39 cases with ARDS were also evaluated.
Missense SNP rs9358856G>A within LRRC16A was associated with favorable survival within 28 days (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.38-0.87; P = 0.0084) and 60 days (P = 0.0021) after ICU admission. Patients with ARDS who carried the variant genotype versus the wild-type genotype showed an attenuated platelet count decline (∆PLT) within 28 days (difference of ∆PLT, -27.8; P = 0.025) after ICU admission. Patients with ∆PLT were associated with favorable ARDS outcomes. Mediation analysis indicated that the SNP prognostic effect was mediated through ∆PLT within 28 days (28-day survival: HR, 0.937; 95% CI, 0.918-0.957; P = 0.0009, 11.53% effects mediated; 60-day survival: HR, 0.919; 95% CI, 0.901-0.936; P = 0.0001, 14.35% effects mediated). Functional exploration suggested that this SNP reduced LRRC16A expression at ICU admission, which was associated with a lesser ∆PLT during ICU hospitalization.
LRRC16A appears to mediate ∆PLT after ICU admission to affect the prognosis in patients with ARDS.
血小板被认为通过炎症凝血途径参与急性呼吸窘迫综合征（ARDS）的发病机制。我们最近报道，富含亮氨酸重复序列16A（LRRC16A）调节基线血小板计数以介导ARDS风险。
研究LRRC16A在ARDS患者生存中的作用及其通过血小板的介导作用。
共纳入414例来自重症监护病房（ICU）的ARDS患者，这些患者有全外显子组基因分型数据、详细的血小板计数以及ICU住院期间的随访数据。分析LRRC16A单核苷酸多态性（SNP）与ARDS预后的关联，以及SNP通过血小板计数的介导作用。还评估了39例ARDS患者的LRRC16A mRNA表达水平。
LRRC16A内的错义SNP rs9358856G>A与ICU入院后28天（风险比[HR]，0.57；95%置信区间[CI]，0.38 - 0.87；P = 0.0084）和60天（P = 0.0021）的良好生存相关。携带变异基因型与野生型基因型的ARDS患者在ICU入院后28天内血小板计数下降（∆PLT）减弱（∆PLT差异为 - 27.8；P = 0.025）。∆PLT患者与良好的ARDS结局相关。中介分析表明，SNP的预后效应在28天内通过∆PLT介导（28天生存：HR，0.937；95% CI，0.918 - 0.957；P = 0.0009，介导效应为11.53%；60天生存：HR，0.919；95% CI，0.901 - 0.936；P = 0.0001，介导效应为14.35%）。功能探索表明，该SNP在ICU入院时降低LRRC16A表达，这与ICU住院期间较小的∆PLT相关。
LRRC16A似乎在ICU入院后介导∆PLT，从而影响ARDS患者的预后。
