Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory Uppsala University, PO Box 815, SE-75108, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, PO Box 582, SE-751 23, Uppsala, Sweden.
Sci Rep. 2018 Apr 3;8(1):5531. doi: 10.1038/s41598-018-23860-y.
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.
很大一部分成年人需要终身服用心血管疾病药物，但这些药物对代谢的影响在很大程度上尚不清楚。本研究旨在确定常见的降压和降脂药物对循环血浆蛋白生物标志物的影响。我们在一个横断面队列中研究了 425 种血浆蛋白，以及人体测量学和生活方式变量，以及遗传特征。我们发现了 8406 个协变量-蛋白关联，两阶段 GWAS 确定了 17253 个 SNP 与 109 种蛋白相关。通过计算去除生活方式和遗传因素引起的变异，我们可以确定药物本身影响了 35.7%的血浆蛋白的丰度水平。药物要么单一影响，要么少数或大量影响，并且对已知疾病途径和生物标志物有负面影响或积极影响。降压或降脂药物影响了 33.1%的蛋白。血管紧张素转换酶抑制剂通过降低肌抑素的血浆水平显示出最强的降低作用。细胞培养实验表明，血管紧张素转换酶抑制剂降低了肌抑素 RNA 水平。因此，了解终身药物治疗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非常重要。
