Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases
Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases
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DOI：
10.1038/s41598-018-23860-y
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发表时间：
2018-04-03
影响因子：
4.6
通讯作者：
Gyllensten, Ulf
中科院分区：
文献类型：
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作者：
Enroth, Stefan;Maturi, Varun;Gyllensten, Ulf
很大一部分成年人口正在接受心血管疾病的终身药物治疗，但其代谢后果在很大程度上是未知的。本研究确定了常见降压和降脂药物对循环血浆蛋白生物标志物的影响。我们研究了血浆中的425种蛋白质，以及人体测量和生活方式变量，以及横断面队列中的遗传特征。我们发现了8,406个协变量-蛋白质关联，一个两阶段的GWAs确定了17253个SNP与109个蛋白质相关。通过计算剔除生活方式和遗传因素的差异，我们可以确定药物本身影响了35.7%的血浆蛋白质的丰度水平。药物要么影响单个、少数或大量蛋白质，要么被发现对已知的疾病途径和生物标记物有负面或正面影响。降压或降脂药物影响33.1%的蛋白质。血管紧张素转换酶抑制剂通过降低血浆中的肌肉生长抑素水平显示出最强的降压作用。细胞培养实验表明，血管紧张素转换酶抑制剂降低了肌肉生长抑素的RNA水平。因此，了解终生用药对血浆蛋白质组的影响对于提高蛋白质生物标志物的诊断精度和疾病管理都是重要的。
A large fraction of the adult population is on lifelong medication for cardiovascular disorders, but the metabolic consequences are largely unknown. This study determines the effects of common anti-hypertensive and lipid lowering drugs on circulating plasma protein biomarkers. We studied 425 proteins in plasma together with anthropometric and lifestyle variables, and the genetic profile in a cross-sectional cohort. We found 8406 covariate-protein associations, and a two-stage GWAS identified 17253 SNPs to be associated with 109 proteins. By computationally removing variation due to lifestyle and genetic factors, we could determine that medication, per se, affected the abundance levels of 35.7% of the plasma proteins. Medication either affected a single, a few, or a large number of protein, and were found to have a negative or positive influence on known disease pathways and biomarkers. Anti-hypertensive or lipid lowering drugs affected 33.1% of the proteins. Angiotensin-converting enzyme inhibitors showed the strongest lowering effect by decreasing plasma levels of myostatin. Cell-culture experiments showed that angiotensin-converting enzyme inhibitors reducted myostatin RNA levels. Thus, understanding the effects of lifelong medication on the plasma proteome is important both for sharpening the diagnostic precision of protein biomarkers and in disease management.