Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics

被引:14
作者
Gordillo-Maranon, Maria [1 ]
Zwierzyna, Magdalena [1 ,2 ]
Charoen, Pimphen [1 ,3 ,4 ]
Drenos, Fotios [1 ,5 ]
Chopade, Sandesh [1 ,2 ]
Shah, Tina [1 ,2 ]
Engmann, Jorgen [1 ,2 ]
Chaturvedi, Nishi [1 ,6 ]
Papacosta, Olia [7 ]
Wannamethee, Goya [7 ]
Wong, Andrew [6 ]
Sofat, Reecha [8 ]
Kivimaki, Mika [9 ]
Price, Jackie F. [10 ]
Hughes, Alun D. [1 ,2 ,6 ]
Gaunt, Tom R. [11 ,12 ,13 ,14 ]
Lawlor, Deborah A. [11 ,12 ,13 ,14 ]
Gaulton, Anna [15 ]
Hingorani, Aroon D. [1 ,2 ]
Schmidt, Amand F. [1 ,2 ,16 ]
Finan, Chris [1 ,2 ,16 ]
机构
[1] UCL, Fac Populat Hlth, Inst Cardiovasc Sci, London WC1E 6BT, England
[2] UCL British Heart Fdn Res Accelerator, London, England
[3] Mahidol Univ, Fac Trop Med, Dept Trop Hyg, Bangkok 10400, Thailand
[4] Mahidol Univ, Integrat Computat BioSci ICBS Ctr, Bangkok 10400, Thailand
[5] Brunel Univ London, Coll Hlth Med & Life Sci, Dept Life Sci, Uxbridge, Middx, England
[6] UCL, MRC Unit Lifelong Hlth & Ageing, London WC1E 7HB, England
[7] UCL, Primary Care & Populat Hlth, London NW3 2PF, England
[8] UCL, Inst Hlth Informat, London WC1E 6BT, England
[9] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England
[10] Univ Edinburgh, Usher Inst, Edinburgh EH8 9AG, Midlothian, Scotland
[11] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England
[12] Univ Bristol, Bristol Med Sch, Populat Hlth, Bristol BS8 2PS, Avon, England
[13] Univ Hosp Bristol Natl Hlth Serv Fdn Trust, Bristol NIHR Bristol Biomed Res Ctr, Bristol BS8 2BN, Avon, England
[14] Univ Bristol, Bristol BS8 2BN, Avon, England
[15] European Bioinformat Inst EMBL EBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England
[16] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands
基金
欧盟地平线“2020”; 英国医学研究理事会; 英国惠康基金; 英国经济与社会研究理事会; 芬兰科学院;
关键词
MENDELIAN RANDOMIZATION; STATIN THERAPY; ASSOCIATION; CHOLESTEROL; RISK; METAANALYSIS; INHIBITION; EZETIMIBE; METFORMIN; EFFICACY;
D O I
10.1038/s41467-021-25731-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Drug target Mendelian randomization (MR) uses genetic variation in or near a gene encoding a drug target to anticipate the effect of drug action on the same target. Using drug target MR, the authors prioritized 30 targets that might elicit beneficial effects in the prevention or treatment of coronary heart disease. Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter the target's expression or function, as a tool to anticipate the effect of drug action on the same target. Here we apply MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets are further prioritized using independent replication, co-localization, protein expression profiles and data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with blood lipids (HDL-C, LDL-C and triglycerides), we robustly prioritize 30 targets that might elicit beneficial effects in the prevention or treatment of CHD, including NPC1L1 and PCSK9, the targets of drugs used in CHD prevention. We discuss how this approach can be generalized to other targets, disease biomarkers and endpoints to help prioritize and validate targets during the drug development process.
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页数:12
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