Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain.
Lancet Respir Med. 2020 Mar;8(3):258-266. doi: 10.1016/S2213-2600(19)30368-6. Epub 2020 Jan 23.
Acute respiratory distress syndrome (ARDS) is a lung inflammatory process caused mainly by sepsis. Most previous studies that identified genetic risks for ARDS focused on candidates with biological relevance. We aimed to identify novel genetic variants associated with ARDS susceptibility and to provide complementary functional evidence of their effect in gene regulation.
We did a case-control genome-wide association study (GWAS) of 1935 European individuals, using patients with sepsis-associated ARDS as cases and patients with sepsis without ARDS as controls. The discovery stage included 672 patients admitted into a network of Spanish intensive care units between January, 2002, and January, 2017. The replication stage comprised 1345 individuals from two independent datasets from the MESSI cohort study (Sep 22, 2008-Nov 30, 2017; USA) and the VISEP (April 1, 2003-June 30, 2005) and MAXSEP (Oct 1, 2007-March 31, 2010) trials of the SepNet study (Germany). Results from discovery and replication stages were meta-analysed to identify association signals. We then used RNA sequencing data from lung biopsies, in-silico analyses, and luciferase reporter assays to assess the functionallity of associated variants.
We identified a novel genome-wide significant association with sepsis-associated ARDS susceptibility (rs9508032, odds ratio [OR] 0·61, 95% CI 0·41-0·91, p=5·18 × 10) located within the Fms-related tyrosine kinase 1 (FLT1) gene, which encodes vascular endothelial growth factor receptor 1 (VEGFR-1). The region containing the sentinel variant and its best proxies acted as a silencer for the FLT1 promoter, and alleles with protective effects in ARDS further reduced promoter activity (p=0·0047). A literature mining of all previously described ARDS genes validated the association of vascular endothelial growth factor A (VEGFA; OR 0·55, 95% CI 0·41-0·73; p=4·69 × 10).
A common variant within the FLT1 gene is associated with sepsis-associated ARDS. Our findings support a role for the vascular endothelial growth factor signalling pathway in ARDS pathogenesis and identify VEGFR-1 as a potential therapeutic target.
Instituto de Salud Carlos III, European Regional Development Funds, Instituto Tecnológico y de Energías Renovables.
急性呼吸窘迫综合征（ARDS）是一种主要由脓毒症引起的肺部炎症过程。大多数先前确定 ARDS 遗传风险的研究都集中在具有生物学相关性的候选基因上。我们旨在确定与 ARDS 易感性相关的新型遗传变异，并提供其在基因调控中作用的补充功能证据。
我们对 1935 名欧洲个体进行了病例对照全基因组关联研究（GWAS），将脓毒症相关 ARDS 患者作为病例，将脓毒症无 ARDS 患者作为对照。发现阶段包括 2002 年 1 月至 2017 年 1 月期间在西班牙重症监护室网络中入院的 672 名患者。复制阶段包括来自 MESSI 队列研究（2008 年 9 月 22 日至 2017 年 11 月 30 日；美国）和 VISEP（2003 年 4 月 1 日至 2005 年 6 月 30 日）和 MAXSEP（2007 年 10 月 1 日至 2010 年 3 月 31 日）SepNet 研究的两个独立数据集的 1345 名个体。发现和复制阶段的结果进行了荟萃分析，以确定关联信号。然后，我们使用肺活检的 RNA 测序数据、计算机分析和荧光素酶报告基因测定来评估相关变异的功能。
我们确定了一个与脓毒症相关 ARDS 易感性相关的新的全基因组显著关联（rs9508032，比值比[OR]0.61，95%置信区间[CI]0.41-0.91，p=5.18×10），位于 Fms 相关酪氨酸激酶 1（FLT1）基因内，该基因编码血管内皮生长因子受体 1（VEGFR-1）。包含哨兵变异及其最佳近缘物的区域充当 FLT1 启动子的沉默子，并且在 ARDS 中具有保护作用的等位基因进一步降低了启动子活性（p=0.0047）。对所有先前描述的 ARDS 基因的文献挖掘验证了血管内皮生长因子 A（VEGFA；OR 0.55，95%CI 0.41-0.73；p=4.69×10）的关联。
FLT1 基因内的常见变异与脓毒症相关 ARDS 相关。我们的研究结果支持血管内皮生长因子信号通路在 ARDS 发病机制中的作用，并确定 VEGFR-1 可能是一个潜在的治疗靶点。
西班牙卡洛斯三世健康研究所、欧洲区域发展基金、能源和可再生技术研究所。
