Drug development is an extremely long and expensive process with a high likelihood of failure at various stages. Genetic variants can modify the expression and/or activity of proteins which may represent potential drug targets and study of these naturally occurring variations in human populations can inform drug development. This area of research can help to prioritise targets based on predicted efficacy, assess safety, identify potential alternative indications (repurposing), and inform the design of clinical studies. CKB has undertaken a phenome-wide assessment (PheWAS) of the effects of several genetic variants related to potential drug targets on a comprehensive range of health outcomes. This work has helped to improve the efficiency and cost-effectiveness of drug development pipelines.
Lp-PLA2 is an enzyme involved in inflammation and the development of atherosclerosis. The drug darapladib, which blocks Lp-PLA2, went through phase three clinical trials to assess its benefits for cardiovascular disease. There is an East Asian genetic variant (V279F in the PLA2G7 gene encoding Lp-PLA2), which also blocks Lp-PLA2 activity. We studied the effects of this genetic variant in 90,000 CKB participants (Millwood et al, Int J Epidemiol 2016). The genetic variant PLA2G7-V279F was not associated with major cardiovascular disease (CVD) events, recorded during seven years of follow-up. Nor was PLA2G7-V279F associated with other major chronic diseases, including diabetes, chronic obstructive pulmonary disease, kidney disease, liver disease, or cancer. These findings complemented the results of clinical trials, which found no major benefit of Lp-PLA2 inhibition for CVD, or any major adverse outcomes. This innovative study demonstrated the value of genetic studies in evaluating potential drug targets.
HDL-cholesterol, often called ‘good’ cholesterol, has been associated with lower risk of CVD. In recent decades, several HDL-cholesterol raising drugs have been developed with the aim of reducing risk of CVD. One approach is to inhibit the protein CETP, which results in higher levels of HDL-cholesterol, and lower levels of LDL-cholesterol (so-called ‘bad cholesterol). An East Asian genetic variant (D459G) results in lower plasma CETP levels and activity, allowing the effects of natural CETP inhibition to be studied. Among 150,000 CKB individuals, CETP-D459G caused higher HDL-cholesterol, but did not affect LDL-cholesterol (Millwood et al, JAMA Cardiol 2018). CETP-D459G was not associated with major CVD events, including stroke and myocardial infarction, but did increase risk of eye diseases, suggesting a potential adverse effect of CETP inhibition. These results complemented the findings of the phase three clinical trials of CETP inhibitors, providing insights into the role of different cholesterol molecules in CVD risk.
Drugs that lower LDL-cholesterol (e.g. statins) have been shown to reduce the risk of cardio-vascular disease. A new approach to lowering LDL-cholesterol is through inhibition of the enzyme PCSK9, which affects how LDL-cholesterol is processed by cells.
We investigated genetic variants in the PCSK9 gene in 100,000 CKB individuals, including an East Asian variant, which resulted in lower activity of PCSK9 and lower LDL cholesterol levels (Holmes et al, in preparation). These variants were associated with less atherosclerosis in the arteries, and lower risk of myocardial infarction and ischaemic stroke. However, there was evidence of excess risks of several respiratory diseases that may represent potential adverse effects. This genetic study adds to the growing body of evidence which supports the use of PCSK9 inhibitors for prevention of CVD, and also informs safety monitoring for clinical trials.
Chymase is an enzyme involved in restructuring damaged tissue structures and may be involved in the development of abnormal heart and renal function. Pharmacological chymase inhibitors were investigated in early phase clinical trials to assess their safety as a potential treatment for heart failure and kidney disease. Two East Asian variants in the chymase gene CMA1 are predicted to inactivate the enzyme, and can be used to help assess the role of chymase inhibition in a range of diseases. In a study of 100,000 CKB individuals (Fairhurst-Hunter et al, under review), these CMA1 variants were not associated with biomarkers of kidney function, or with kidney disease, heart failure or other CVD. Evidence from our findings has contributed to decisions about whether to develop chymase inhibitors further in phase three clinical trials.
Implications for future work
This work in CKB work highlights the importance of genetic approaches in ancestrally diverse cohorts to provide insights into drug target development. While continuing with hypothesis-driven assessments of known or potential drug-target-related variants, we will also apply a hypothesis-free approach to assess much larger numbers of functional variants captured in the CKB array, particularly those present, with reasonably high frequency, only in East Asians. We envisage that such an approach, particularly in combination with novel proteomic data (involving thousands of proteins), may lead to the discovery of novel drug targets for specific diseases.