Comparing the Effect Profile of CETP in Individuals of East Asian and European Ancestries

Background: Cholesteryl ester transfer protein (CETP) is a lipid drug target under development for coronary heart disease (CHD) in both European and East Asian populations. Previous drug target Mendelian randomization (MR) studies conducted in East Asians failed to show a CHD effect, which has been interpreted as lack of effectiveness of CETP inhibition for CHD prevention in this population. Objectives: In this study, we inferred the effect of CETP inhibition in individuals of European and East Asian ancestries using drug target Mendelian randomization. Methods: We leveraged genetic associations of CETP variants with major blood lipid fractions for individuals of European (n=1,320,016) and East Asian (n=146,492) ancestries. Colocalization was employed to identify potential cross-ancestry signals of CETP variants for plasma concentrations of low-density lipoprotein cholesterol (LDL-C) or high-density lipoprotein cholesterol (HDL-C). Drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition. Differences between ancestries were evaluated using interaction tests, applying a multiplicity corrected alpha of 1.9x10-3 based on the 26 considered traits. Results: There was strong support (posterior probability: 1.00) of a shared causal CETP variant affecting HDL-C in both populations, which was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP was associated with lower LDL-C, Lp[a], systolic blood pressure and pulse pressure in both groups, but the effects were more pronounced in European individuals (interaction p-values < 1.9x10-3). Lower CETP was protective against CHD, angina, intracerebral haemorrhage and heart failure in both ancestries, for example for CHD in East Asians (OR 0.89, 95%CI 0.84;0.94) compared to Europeans (OR 0.95, 95%CI 0.92;0.99, interaction p-value=0.05). Conclusions: In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries. ### Competing Interest Statement AFS and CF have received unrestricted funding from NewAmsterdam, which is currently developing the CETP-inhibitor obicetrapib. The views expressed in this study are the personal views of MGM and do not represent the views of her current employer, the European Medicines Agency. All the authors declare no other competing interests. ### Funding Statement This research was funded by the Medical Research Council Doctoral Training Programme, grant MR/NO13867/1, awarded to DD. KK is supported by the European Research Council under the European Union Horizon 2020 research and innovation program grant 948561. ADH is a NIHR Senior Investigator and supported by the UKRI-NIHR grant MR/V033867/1 for the Multimorbidity Mechanism and Therapeutics Research Collaboration. CF acknowledges support from UCL BHF Research Accelerator grant AA/18/34223, and MR/V033867/1. AFS is supported by the BHF grants PG/18/5033837, PG/22/10989, AA/18/34223, and MR/V033867/1. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at: https://pan.ukbb.broadinstitute.org/, http://www.nealelab.is/uk-biobank, https://www.nature.com/articles/s41588-021-00931-x, https://www.sciencedirect.com/science/article/pii/S0002929718303203?via%3Dihub, https://www.globalbiobankmeta.org/, https://www.nature.com/articles/s41588-020-0640-3#article-info, https://www.nature.com/articles/ng.3396, https://www.ncbi.nlm.nih.gov/pubmed/31959993, https://www.nature.com/articles/s41588-022-01058-3, https://www.nature.com/articles/s41588-021-00852-9#Abs1, https://www.nature.com/articles/s41467-019-13690-5 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript