Abstract
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.
Highlights
A large fraction of the human population medicates for chronic diseases such as high blood pressure or high blood lipids
Of 145 biomarker candidates for cancer and cardiovascular disease measured in plasma, we previously found that 75% were affected by lifestyle or genetic factors, and that these factors explained
To test the effect of angiotensin-converting enzyme (ACE)-inhibitors on myostatin levels we studied the effect of enalapril on RNA-levels in the BT549 cell line
Summary
A large fraction of the human population medicates for chronic diseases such as high blood pressure or high blood lipids. Elevation of blood pressure has been associated with increased cardiovascular morbidity and mortality, including cardiovascular death, myocardial infarction, heart failure and stroke[1], and is the largest single contributor to worldwide disease burden and mortality[2] affecting nearly 25% of the adult population of the United States. Clinical management of these diseases involves pharmacotherapy with mono- or combination therapy with Thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blockers, with proven efficacy at reducing blood pressure, but potentially increasing the risk of cardiovascular events[3,4,5]. To assess the effect of medication for common diseases, and in particular the effect of antihypertensive and lipid-lowering treatment, on the plasma proteome, we analyzed 425 proteins from 178 KEGG pathways, representing a cross-section of the plasma proteome, in a cross-sectional cohort of over 900 individuals for which detailed data on anthropometrics, lifestyle, use of medication, and genetic variants was known
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