急性呼吸窘迫综合征
医学
孟德尔随机化
血管生成素2
调解
麻醉学
止痛药
重症监护医学
败血症
因果推理
内科学
麻醉
病理
肺
遗传学
血管内皮生长因子
血管内皮生长因子受体
法学
基因型
基因
生物
政治学
遗传变异
作者
John P. Reilly,Fan Wang,T.K. Jones,Jessica A. Palakshappa,Brian J. Anderson,Michael G. S. Shashaty,Thomas Dunn,Erik D. Johansson,Thomas Riley,Brian Lim,Jason Abbott,C.A.G. Ittner,Edward Cantu,Xihong Lin,Carmen Mikacenic,Mark M. Wurfel,David C. Christiani,Carolyn S. Calfee,Michael A. Matthay,Jason D. Christie,Rui Feng,Nuala J. Meyer
标识
DOI:10.1007/s00134-018-5328-0
摘要
A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on the basis of experimental and observational evidence. We used genetic causal inference methods—Mendelian randomization and mediation—to infer potential effects of plasma ANG2. We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p < 0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis. Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n = 404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09–0.36, p = 0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p = 0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06–4.78), p = 0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk. In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.
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