Table 1.

Comparison of the findings from randomized controlled trials (RCTs) and Mendelian randomization (MR) of the corresponding therapeutic target

Drug target	Orthodox drug development					MR
	Compound(s) evaluated	Developmental stage	Therapeutic area	Outcomes assessed in preclinical studies or RCTs of selective drug interventions	Findings from preclinical studies or RCTs of selective drug interventions	Encoding gene	Outcomes evaluated in MR	Findings from MR	Inferences drawn from comparison of the findings from preclinical studies or RCTs and MR
Cholesteryl ester transfer protein (Sofat et al. 2010)	Torcetrapib	Phase III	Cardiovascular disease (CVD)	Blood lipids (total-, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), triglycerides; blood pressure; CVD events	HDL elevation, triglyceride and LDL reduction; unintended blood pressure elevation; unintended increase in CVD events	CETP (Barter et al. 2007)	Blood lipids (total-, LDL-C, and HDL-C, triglycerides); blood pressure	Associations with blood lipids consistent with effects in RCTs; no genetic association with blood pressure	Blood pressure elevating effect of torcetrapib is off target
Hydroxy methyl (HMG)-coA reductase (Swerdlow et al. 2015)	Statins	Phase IV (post-marketing)	CVD	Blood lipid fractions, weight, type 2 diabetes risk	Statin treatment in RCTs linked to increased weight and risk of type 2 diabetes	HMGCR (Swerdlow et al. 2015)	Blood lipid fractions, anthropometric measures, glucose and insulin, type 2 diabetes risk	HMGCR single-nucleotide polymorphisms (SNPs) associated with lower LDL-C, higher weight, fasting glucose and insulin, and type 2 diabetes risk	Increased risk of type 2 diabetes is an unintended on-target effect of statins mediated in part through weight gain
Niemann–Pick C1-like 1 (Cannon et al. 2015)	Ezetimibe	Phase III	CVD	LDL-C, cardiovascular death, nonfatal myocardial infarction, unstable angina requiring hospitalization and revascularization	Ezetimibe added to statins produces modest additional benefit in cardiovascular outcomes in patients following an acute coronary syndrome (ACS)	NPC1L1 (The Myocardial Infarction Genetics Consortium Investigators et al. 2014)	Plasma lipid levels and risk of coronary heart disease (CHD)	Inactivating mutations in NPC1L1 are associated with lower LDL-C and protection from myocardial infarction risk	Niemann–Pick C1-like 1 is a validated target for LDL-C lowering and CHD prevention
Proprotein convertase subtilisin/kexin type 9 serine protease (Schmidt et al. 2017a)	Alirocumab, evolocumab	Phase II	Lipid lowering and CVD	LDL-C	Alirocumab and evolocumab reduce LDL-C among patients with heterozygous familial or polygenic hypercholesterolemia and reduce cardiovascular events in patients with or at high risk of CVD	PCSK9 (Cohen et al. 2006)	LDL-C and risk of CHD	Inactivating mutations in PCSK9 associated with reduced LDL-C and CHD risk	Proprotein convertase subtilisin/kexin type 9 serine protease is a validated target for LDL-C lowering and reduction in cardiovascular risk
Glucagon-like peptide-1 receptor (Marso et al. 2016)	Liraglutide	Phase III	Diabetes and CVD	Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke	Liraglutide reduced risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus	GLP1R (Scott et al. 2016)	Body weight, glycemic traits, lipids, blood pressure, risk of type 2 diabetes, and CHD	A low frequency, coding region missense variant in GLP1R is associated with lower fasting glucose, diabetes risk, and risk of CHD	GLP1R is a validated target for treatment of diabetes and reducing CHD risk
Lipoprotein- associated phospholipase A2 (Lp-PLA2) (O'Donoghue et al. 2014; STABILITY Investigators et al. 2014)	Darapladib	Phase III	CVD	Major cardiovascular events or major coronary events	No reduction in CVD events in patients with stable coronary disease or recent ACS, despite reductions in Lp-PLA2 mass and activity	PLA2G7 (Casas et al. 2010; Millwood et al. 2016a)	Lp-PLA2 concentration, blood lipids, inflammation markers, and CHD events	PLA2G7 variants were not associated with alterations in cardiovascular risk markers or CHD events	Lp-PLA2 is not involved in the development of CVD; low priority as therapeutic target for this indication
Interleukin 6 receptor (IL-6R) (Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium et al. 2012)	Tocilizumab	Phase III	Autoimmune disease	Blood lipid fractions and inflammation markers including IL- 6, C-reactive protein (CRP), and fibrinogen	In patients with rheumatoid arthritis, tocilizumab-induced alterations in circulating inflammation markers characteristic of IL-6 blockade	IL6R (Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium et al. 2012)	Blood lipid fractions and inflammation markers including IL-6, CRP, and fibrinogen; cardiovascular events including CHD events and abdominal aortic aneurysm	Variants in the IL6R gene that recapitulate the biomarker profile of IL-6R blockade were associated with a reduction in CHD events	IL-6R signaling is involved in the development of CHD; the IL-6R blocker tocilizumab could be repurposed for the treatment of CVD
CRP (Casas et al. 2008)	No CRP inhibitors yet available for clinical use	Preclinical	CVD	Effects of CRP on processes believed to contribute to atherosclerosis studied in vitro or in animals; associations of CRP with CVD in human observational studies	Observational associations of CRP with CVD events in humans, but studies prone to confounding; pro-atherogenic effect of CRP in vitro and in animals later proved to be artefactual	CRP (C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) et al. 2011)	Inflammation and coagulation markers, blood lipid fractions, and CHD events	SNPs in the CRP gene exclusively associated with CRP exhibited no association with CHD; no causal association of CRP with CHD based on instrumental variables analysis	CRP is not causal in CHD pathogenesis; priority as a therapeutic target for CHD prevention diminished
Secretory phospholipase A2 (sPLA2) (Nicholls et al. 2014)	Varespladib	Phase III	CVD	sPLA2 concentration, blood lipids, inflammation markers, and CVD events	No beneficial effect of varespladib on CVD events in patients with recent ACS, despite a drug- induced reduction in sPLA2 concentration and activity	PLA2G2A (Holmes et al. 2013)	sPLA2 mass and activity and major vascular events (MVEs) in general populations and patients with ACS	SNPs in the PLA2G2A gene were associated with substantial alterations in sPLA2 mass and activity but not with MVEs	sPLA2 is not involved in the development of CVD; dismissed as a therapeutic target in CVD
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Martin et al. 2014)	Ivabradine	Phase IV (post-marketing)	CVD	Risk of atrial fibrillation	Developed for angina and heart failure, post hoc meta-analysis of RCTs (motivated by genetic findings (Casas et al. 2008; Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium et al. 2012) indicated ivabradine treatment is associated with a higher risk of atrial fibrillation	HCN4 (Ellinor et al. 2012; den Hoed et al. 2013)	Atrial fibrillation (genome-wide association analysis)	Variants in the gene HCN4 encoding the target of ivabradine associated with a higher risk of atrial fibrillation	Atrial fibrillation is a mechanism-based adverse effect of ivabradine treatment
Tumor necrosis factor receptor 1 (TNFR1) and TNF (van Oosten et al. 1996; The Lenercept Multiple Sclerosis Study Group 1999)	Monoclonal antibodies against TNF-α	Phase III and phase IV	Neurological disease	Multiple sclerosis (MS) exacerbations	MS exacerbations	TNFRSF1A (Gregory et al. 2012)	MS	A variant in the TNFRSF1A that encodes the TNFR1 gene indicates expression of a soluble form of TNFR1 that blocks the effect of TNF, and associates with a higher risk of MS; the mechanism mimics that of monoclonal antibodies against TNF	Exacerbation of MS induced by anti-TNF monoclonal antibodies is mechanism based