Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer’s disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.


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(http://amdgenetics.org/), and genetic associations with NMR measured circulating lipoprotein subfractions and other metabolites were available from a metaanalysis of Kettunen et al.45,and UCLEB46 (n: 33,029, http://www.computationalmedicine.fi/data/NMR_GWAS/). Additionally, the following resources were sourced: major circulating lipid sub-fractions or apolioproteins (LDL-C, HDL-C, triglycerides, lipoprotein A [Lp(a)], apolipoprotein B, apolipoprotein A1), pulse rate, glucose and HbA1c, leukocytes, lymphocytes, monocytes, neutrophil counts, and C-reactive protein, using data from the UK biobank (UKB -http://www.nealelab.is/ uk-biobank The manuscript represent meta-analyses of publicly available trial data in the form of point estimates and standard errors, and drug target MR analyses using similarly publicly available data on the genetic association of CETP and PCSK9 variants with protein concentration and clinically relevant traits. This re-use of publicly available data provides an important opportunity to gain additional insights without additional burden or risk to participants. As such we did not perform any de novo participant recruitment, nor related sample size calculations. Precision of our results is indicated by 95% confidence intervals, where wide confidence intervals provide a clear indication results can be improved by increasing sample size beyond the currently available number. To improve coomputational stability, low MAF (below 0.01) variants were excluded (a priori defined).
The presented drug target Mendelian randomization analyses sourced publicly available data on the genetic association with CETP concentration or with PCSK9 concentration from: Blauw et al: https://pubmed.ncbi.nlm.nih.gov/29728394/ Pott et al: https://pubmed.ncbi.nlm.nih.gov/29748315/ The CETP drug target analysis was replicated using three proxies of protein concentration and activity. Specifically, we used genetic variants associated with LDL-C, HDL-C, or TG selected form the same 2.5 kb flanking region around CETP used to identify genetic instruments for protein concentration from Blauw et al. The PCSK9 analysis was replicated using genetic association with LDL-C selected from the same 2.5 kb PCSK9 flanking region used to identify genetic association with protein concentration from Pott et all.
The manuscripts includes a meta-analysis of randomized controlled trials, were subjects were randomly allocated to CETP inhibition or placebo groups. Furthermore, we conducted drug target mendelian randomization, where -following Mendel law's of inheritance, genetic variants are assumed to be randomly allocated during gamete formation, resulting in a naturally occurring randomized experiment.
The manuscript describes a meta-analyses of aggregated data (point estimates and standard errors) of blinded placebo controlled trials, where both participants and study personal were blinded for treatment allocation. The current researchers were not involved with these trials and hence had no knowledge of allocation. Additionally, we performed drug target Mendelian randomization leveraging aggregated genetic associations (again point estimates and standard errors) with CETP or PCSK9 concentration to anticipate effects of inhibiting these drug targets would have clinically relevant outcomes. Following Mendel's laws of inheritance genetic loci are inherited randomly, resulting in a natural experiment or pseudo randomized experiment. In this setting the exposure of interest is the genetic variant encoding a drug target; both the research and the subjects were unaware of their genotype.