AJRCCM:全血RNA测序与肺动脉高压和临床结局分析

2021-10-31 刘少飞 MedSci原创

特发性和遗传性肺动脉高压(PAH)是罕见的,但构成了一个遗传异质性的患者组。与潜在遗传结构相关的RNA测序可以通过识别关键的信号通路来更好地理解潜在的病理,并根据临床风险更有力地对患者进行分层。

肺动脉高压 (PAH) 与远端肺动脉的血管收缩和闭塞有关,其特征是内皮损伤、平滑肌和成纤维细胞增殖以及炎症。肺血管阻力增加导致右心衰竭,即使采用现代疗法,估计 5 年的存活率为 52-75%。患者之间的恶化速度和对治疗的反应各不相同,这促使人们寻找更好的临床结果预测指标和为药物选择提供信息的工具。使用多种组学技术的分子分析比标准临床表型提供了更大的粒度来表征 PAH 患者,可以改善初始风险分层、治疗选择和监测,并提供对当前疗法尚未靶向的生物学途径的见解。

通过 RNA 测序的转录组分析允许对组织样本中的基因表达进行全面分析。全血 RNA 分析提供了一种替代肺活检的“液体活检”,肺活检在 PAH 中具有高风险,并且可以顺序进行。这种方法还可以研究最近强调的 PAH 中的免疫机制。先前对 PAH 中血液 RNA 的研究受到患者数量和微阵列使用的限制,这些微阵列不如高质量 RNA 测序 (RNAseq) 敏感,并且受到每个特定阵列的探针组的限制。最近对这些微阵列研究的荟萃分析确定了一些一致的差异表达基因,这些基因在个别研究中未被重视。来自晚期 PAH 患者的移植肺组织也显示出 RNA 谱的差异。这两项研究的结果仍有待独立队列的验证。

本研究的目的是表征与 PAH 相关的基因通路,并评估它们与疾病异质性的关联,特别是在疾病严重程度和结果方面,包括对血管扩张剂和死亡率的反应,以及遗传背景。

本研究将来自英国 PAH 队列研究的 359 名特发性、遗传性或药物诱导的 PAH 患者的全血样本中的基因表达与 72 名年龄和性别匹配且没有任何心脏或呼吸系统疾病的健康志愿者作为对照对象进行比较。将样本均匀分布到三阶段设计中,通过 RNAseq 确定了可重复的 RNA 表达差异。两种不同的计算方法用于估计白细胞 (WBC) 分数,从而解释不同细胞数量对样本中基因转录水平的潜在影响。在单独的病例对照分析中,结合基因表达差异的预测统计模型在识别 PAH 患者方面表现良好。基于 RNA 的评分也与疾病严重程度和临床结果(全因死亡率)相关。检测到决定 PAH RNA 水平的遗传变异的富集,表明这些 RNA 与疾病的发病机制有关。

研究设计:

Figure

肺动脉高压(PAH)患者和对照组不同水平的RNAs的鉴定

Figure

LASSO模型在年龄和性别匹配受试者的独立验证组中的表现

Figure

肺动脉高压 (PAH) 的诊断 RNA 模型和存活率:为了确定模型中的 25 个转录本中的哪些与生存相关,在随访期间测试了每个转录本与全因死亡率的关联。为了进一步表征 RNA 特征,我们分析了其与疾病严重程度的三个临床指标的关联——WHO 功能等级、运动能力(步行 6 分钟)和心脏生物标志物(BNP 或 NT-proBNP)。

Figure

本研究报告了一种将特发性和遗传性 PAH 与健康个体区分开来的 RNA 特征。 该特征还根据疾病严重程度和早逝风险对患者进行分层,增加了其与 PAH 关联的可信度。 几种有区别的 mRNA 编码 TF,包括 SMAD5、HIF-1α 和 KLF10。 整合基因组数据并确定潜在致病信号通路的 MR 分析显示,与 SMAD5 低表达水平相关的遗传变异在 PAH 患者中更为常见。

文献出处:

Rhodes CJ, Otero-Núñez P, Wharton J, Swietlik EM, Kariotis S, Harbaum L, Dunning MJ, Elinoff JM, Errington N, Thompson AAR, Iremonger J, Coghlan JG, Corris PA, Howard LS, Kiely DG, Church C, Pepke-Zaba J, Toshner M, Wort SJ, Desai AA, Humbert M, Nichols WC, Southgate L, Trégouët DA, Trembath RC, Prokopenko I, Gräf S, Morrell NW, Wang D, Lawrie A, Wilkins MR. Whole-Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome. Am J Respir Crit Care Med. 2020 Aug 15;202(4):586-594. doi: 10.1164/rccm.202003-0510OC. PMID: 32352834; PMCID: PMC7427383.

 

 

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