Approved research

Pharmacogenomic Genome-wide Association Analyses of Drug Responses and Adverse Events Using UK Biobank Data

Lay summary

Cardiovascular diseases were the leading cause of morbidity and mortality worldwide. Hypertension or high blood pressure, one of the major modifiable cardiovascular risk factors, was among the leading causes of disease burden in the UK. Even though hypertension can be managed through at least five classes of blood pressure lowering medications, the response rate to any of these drug class is < 50%. Another leading cause of deaths globally is cancer. With advances in early detection and new treatment options, the number of cancer survivors continues to increase. Unfortunately, many cancer survivors die from cardiovascular complications arising from the cancer therapies. Pharmacogenomics, or the genetic/genomic determinants of drug response and adverse effects, is a tool that has been useful in individualizing medication therapy, and is an area of Precision Medicine that is most likely to see near-term success. The aims of this proposed study are to identify and/or validate genetic variants associated with pharmacogenomic traits such as drug responses and adverse events, using UK Biobank data. Specifically, we aim to 1) validate the pharmacogenomic markers for blood pressure responses to antihypertensive medications discovered in the International Consortium of Antihypertensive Pharmacogenomic Studies (ICAPS) and 2) identify pharmacogenomic markers associated with cancer therapy related cardiotoxicity. In order to identify genetic variants associated with certain trait of interest, we will evaluate each genetic variant in a genome-wide fashion in the participants who were eligible for each analysis. This type of analysis will be performed for each trait including blood pressure responses to certain antihypertensive medication or adverse event of interest related to cancer therapies. We expect to complete the proposed work within 36 months. At the end of the proposed work, we expect to have validated some of the pharmacogenomic markers for antihypertensive treatments and have discovered markers for cancer therapy related cardiotoxicity. These findings will enhance our understanding of the underlying mechanisms of antihypertensive treatments, cancer therapies related cardiotoxicity, and provide an opportunity to improve treatment of patients in a personalized manner. The impact of such discovery will likely result in different treatment approaches that will reduce the risk of drug-induced adverse events, reduce morbidity/mortality, improve outcome and reduce cost for the health care system. This is in line with the UK Biobank's intention to improve the prevention, diagnosis and treatment of illness and promotion of health throughout society.