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

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Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease
Nature Communications ( IF 14.7 ) Pub Date : 2021-09-24 , DOI: 10.1038/s41467-021-25703-3
Amand F Schmidt _{1,

2,

3} , Nicholas B Hunt ₄ , Maria Gordillo-Marañón _{1,

2} , Pimphen Charoen _{1,

5,

6} , Fotios Drenos _{1,

7} , Mika Kivimaki ₈ , Deborah A Lawlor _{9,

10,

11} , Claudia Giambartolomei ₁₂ , Olia Papacosta ₁₃ , Nishi Chaturvedi _{1,

14} , Joshua C Bis ₁₅ , Christopher J O'Donnell _{16,

17} , Goya Wannamethee ₁₃ , Andrew Wong ₁₄ , Jackie F Price ₁₈ , Alun D Hughes _{1,

2,

14} , Tom R Gaunt _{9,

10,

11} , Nora Franceschini ₁₉ , Dennis O Mook-Kanamori ₂₀ , Magdalena Zwierzyna _{1,

2} , Reecha Sofat ₂₁ , Aroon D Hingorani _{1,

2,

22} , Chris Finan _{1,

2,

3,

22}

Affiliation

Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.
UCL British Heart Foundation Research Accelerator, London, UK.
Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Integrative Computational BioScience (ICBS) Center, Mahidol University, Bangkok, Thailand.
Department of Life Sciences, College of Health, Medicine, and Life Sciences, Brunel University London, Uxbridge, UK.
Department of Epidemiology and Public Health, University College London, London, UK.
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Population Health, Bristol Medical School, University of Bristol, Bristol, UK.
Bristol NIHR Bristol Biomedical Research Centre, University Hospitals Bristol National Health Service Foundation Trust and University of Bristol, Bristol, UK.
Istituto Italiano di Tecnologia, Central RNA Lab, Genova, Italy.
Primary Care and Population Health, University College London, London, UK.
MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Medicine, VA Boston Healthcare System, Boston, MA, USA.
Usher Institute, University of Edinburgh, Edinburgh, UK.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Institute of Health Informatics, University College London, London, UK.
Health Data Research UK, London, UK.

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.

中文翻译：

胆固醇酯转移蛋白（CETP）作为心血管疾病的药物靶点

用于治疗冠心病 (CHD) 的胆固醇酯转移蛋白 (CETP) 抑制剂的开发尚未获得许可。为了区分化合物和药物靶点失败，我们比较了临床试验的证据和药物靶点CETP蛋白浓度的孟德尔随机化，并将其与前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）的孟德尔随机化进行比较。我们表明，CETP 抑制剂先前的失败可能与化合物相关，正如试验中观察到的化合物对血脂、血压和临床结果的影响存在显着程度的异质性所表明的那样。通过孟德尔随机化评估的靶向 CETP 抑制有望降低冠心病、心力衰竭、糖尿病和慢性肾病的风险，同时增加年龄相关性黄斑变性的风险。相比之下，较低的 PCSK9 浓度预计会降低患冠心病、心力衰竭、心房颤动、慢性肾病、多发性硬化症和中风的风险，同时可能增加患阿尔茨海默病和哮喘的风险。由于对脂蛋白代谢谱有不同的影响，CETP 和 PCSK9 的联合抑制可能会带来额外的好处。总之，我们提供的遗传证据表明，CETP 是预防 CHD 的有效目标，但对年龄相关性黄斑变性具有潜在的目标不利影响。

更新日期：2021-09-24

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