1.
Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment.
Sliz, E, Kettunen, J, Holmes, MV, Williams, CO, Boachie, C, Wang, Q, Männikkö, M, Sebert, S, Walters, R, Lin, K, et al
Circulation. 2018;(22):2499-2512
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Abstract
BACKGROUND Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. METHODS 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. RESULTS Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2x10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA) whereas statin treatment weakly lowered GlycA levels. CONCLUSIONS Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on VLDL lipids compared with statins for an equivalent lowering of LDL-C, which potentially translate into smaller reductions in cardiovascular disease risk.
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Urinary proteomics and metabolomics studies to monitor bladder health and urological diseases.
Chen, Z, Kim, J
BMC urology. 2016;:11
Abstract
BACKGROUND Assays of molecular biomarkers in urine are non-invasive compared to other body fluids and can be easily repeated. Based on the hypothesis that the secreted markers from the diseased organs may locally release into the body fluid in the vicinity of the injury, urine-based assays have been considered beneficial to monitoring bladder health and urological diseases. The urine proteome is much less complex than the serum and tissues, but nevertheless can contain biomarkers for diagnosis and prognosis of diseases. The urine metabolome has a much higher number and concentration of low-molecular metabolites than the serum or tissues, with a far lower lipid concentration, yet informs directly about dietary and microbial metabolism. DISCUSSION We here discuss the use of mass spectrometry-based proteomics and metabolomics for urine biomarker assays, specifically with respect to the underlying mechanisms that trigger the pathological condition. CONCLUSION Molecular biomarker profiles, based on proteomics and metabolomics studies, reliably distinguish patients from healthy controls, stratify sub-populations with respect to treatment options, and predict therapeutic response of patients with urological disease.