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 specific drug targets under clinical development on a comprehensive range of health outcomes. This work has helped to inform drug development pipelines, and improve efficiency and cost-effectiveness. Our more recent work has used proteo-genomic approaches to identify potential novel drug targets for treatment and prevention of a range of different diseases, including ischaemic heart disease, obesity, diabetes, and stroke.
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 (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. PLA2G7-V279F was also not 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 the 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 (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 CVD. A new approach to lowering LDL-cholesterol is through inhibition of the enzyme PCSK9, which affects how LDL-cholesterol is processed by cells.
Drugs that lower LDL-cholesterol (e.g. statins) have been shown to reduce the risk of CVD. 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 (Eur J Prev Cardiol 2024). 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
(J Cardiovasc Translat Res 2022), 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.
Our recent work uses measurements of 3,000 proteins from the Olink Explore platform, and 7,000 proteins from the SomaScan platform among 4,000 participants (including 2,000 IHD cases and a subcohort of 2,000). We showed that these two proteomics platforms provide complementary information for about 2,000 overlapping proteins on the associations of proteins with genetic and non-genetic factors, and IHD risks (Nature Comms 2024), which can inform future proteo-genomic study designs. An integrated analysis using genetic and proteomic datasets in CKB identified several potential novel drug targets for IHD, which were replicated in European ancestry adults (J Am Coll Cardiol 2023). These targets included Furin, a protein with an important role in cardiovascular pathways, which we have reviewed in relations to its potential for prevention and treatment of cardiovascular disease (Int J Mol Sci 2024). Using a similar proteo-genomic approach, we have also identified a number of proteins which were causally related to adiposity (Genetic Epidemiology 2023) and diabetes (Diabetes Care 2024) in Chinese adults, most of which were replicated in other populations, and which may represent potential drug targets for obesity and diabetes.
Implications for future work
This work in CKB work highlights the importance of genetic, proteomic, and biomarker 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, as well as utilising the whole genome sequencing data to identify rarer variants. Combining genomics with novel multi-omic data may lead to the discovery and evaluation of novel drug targets for a wide range of diseases.