1 Department of Medicine.
2 Center for Biomedical Informatics and Biostatistics.
Am J Respir Crit Care Med. 2018 Jun 1;197(11):1421-1432. doi: 10.1164/rccm.201705-0961OC.
Genetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches.
To identify genetic susceptibility targets for ARDS.
A genome-wide association study was performed on 232 African American patients with ARDS and 162 at-risk control subjects. The Identify Candidate Causal SNPs and Pathways platform was used to infer the association of known gene sets with the top prioritized intragenic SNPs. Preclinical validation of SELPLG (selectin P ligand gene) was performed using mouse models of LPS- and ventilator-induced lung injury. Exonic variation within SELPLG distinguishing patients with ARDS from sepsis control subjects was confirmed in an independent cohort.
Pathway prioritization analysis identified a nonsynonymous coding SNP (rs2228315) within SELPLG, encoding P-selectin glycoprotein ligand 1, to be associated with increased susceptibility. In an independent cohort, two exonic SELPLG SNPs were significantly associated with ARDS susceptibility. Additional support for SELPLG as an ARDS candidate gene was derived from preclinical ARDS models where SELPLG gene expression in lung tissues was significantly increased in both ventilator-induced (twofold increase) and LPS-induced (5.7-fold increase) murine lung injury models compared with controls. Furthermore, Selplg mice exhibited significantly reduced LPS-induced inflammatory lung injury compared with wild-type C57/B6 mice. Finally, an antibody that neutralizes P-selectin glycoprotein ligand 1 significantly attenuated LPS-induced lung inflammation.
These findings identify SELPLG as a novel ARDS susceptibility gene among individuals of European and African descent.
遗传因素与急性呼吸窘迫综合征（ARDS）易感性有关。鉴定与风险增加和严重程度相关的新候选基因，将有助于我们理解 ARDS 的病理生理学，并加强开发新的预防和治疗方法的努力。
确定 ARDS 的遗传易感性靶标。
对 232 名非裔美国人 ARDS 患者和 162 名高危对照进行了全基因组关联研究。使用“确定候选因果 SNP 和途径”平台推断已知基因集与优先考虑的基因内 SNP 的关联。使用 LPS 和呼吸机诱导的肺损伤小鼠模型对 SELPLG（选择素 P 配体基因）进行了临床前验证。在独立队列中，对区分 ARDS 患者和脓毒症对照的 SELPLG 内外显子变异进行了确认。
途径优先级分析确定了 SELPLG 内的非同义编码 SNP（rs2228315）与易感性增加相关，该 SNP 编码 P-选择素糖蛋白配体 1。在独立队列中，两个外显子 SELPLG SNP 与 ARDS 易感性显著相关。SELPLG 作为 ARDS 候选基因的额外支持来自 ARDS 临床前模型，其中通气诱导（增加两倍）和 LPS 诱导（增加 5.7 倍）的小鼠肺损伤模型中肺组织中的 SELPLG 基因表达均显著高于对照组。此外，Selplg 小鼠的 LPS 诱导的炎症性肺损伤明显低于野生型 C57/B6 小鼠。最后，中和 P-选择素糖蛋白配体 1 的抗体可显著减轻 LPS 诱导的肺炎症。
这些发现确定 SELPLG 为欧洲和非洲裔个体中一种新的 ARDS 易感性基因。
