JAHA:孟德尔随机研究与临床随访将代谢物与肺动脉高压的风险和严重程度联系起来

2024-03-10 刘少飞 MedSci原创 发表于上海

该研究利用 Mendelian randomization 分析探索了肺动脉高压患者血清中代谢物与疾病严重程度的关联,并发现了潜在的治疗靶点和策略。

背景:肺动脉高压(PAH)表现出表型异质性和对治疗的可变反应。代谢组在PAH的发病机制中起着重要作用,但以往的研究缺乏足够的力量来确认特定代谢物的作用。Mendelian randomization(MR)是一种用于评估暴露与结果之间因果关系的方法。

方法和结果:利用全基因组关联研究汇总统计数据,我们实施了MR分析,以测试575种代谢物的血清浓度与PAH之间潜在的因果关系。经过多重检验校正后,发现五种代谢物与PAH的风险存在因果关系。接下来,我们在一个独立的临床队列中,对449名PAH患者的血清中候选代谢物的浓度进行测量,以检查代谢物浓度是否与疾病严重程度的标志物相关。在我们的MR研究中,通过直接测量,我们发现了五个候选物质中的两个与PAH的临床严重程度相关,其中丝氨酸与PAH的临床严重程度呈负相关,而同柱草碱则呈正相关。最后,我们使用条件和正交方法探索了我们主导的代谢物背后的生物学。我们使用578例PAH病例和361,675例对照进行了全外显子测序数据的稀有变异负荷测试。多变量MR是MR的一种扩展,它使用一组工具单核苷酸多个曝露的测量; 多变量MR用于确定不同暴露的效应对单一结果的相互依赖关系。稀有变异分析表明,在丝氨酸饥饿条件下,激活转录因子4内的失活突变与PAH的较高风险相关。同柱草碱是一种异源代谢物,其结构与l-脯氨酸甜菜碱相关,后者以前已被联系到PAH中炎症和组织重塑的调节。我们的多变量MR分析表明,l-脯氨酸甜菜碱的效应实际上是通过同柱草碱间接介导的。

结论:我们的数据提供了在PAH背景下研究代谢组的方法,并提出了几个进一步评估和转化研究的候选物质。这些发现有助于更深入地理解PAH的病理生理机制,为未来的临床治疗提供了潜在的靶点和策略。

原始出处:

Alhathli E, Julian T, Girach ZUA, Thompson AAR, Rhodes C, Gräf S, Errington N, Wilkins MR, Lawrie A, Wang D, Cooper-Knock J. Mendelian Randomization Study With Clinical Follow-Up Links Metabolites to Risk and Severity of Pulmonary Arterial Hypertension. J Am Heart Assoc. 2024 Mar 8:e032256. doi: 10.1161/JAHA.123.032256. Epub ahead of print. PMID: 38456412.

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    2024-03-10 yangchou 来自浙江省

    好文章,谢谢分享。

    0

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    2024-03-10 1209e435m98(暂无昵称) 来自浙江省

    学习了,谢谢分享

    0