Challenges and opportunities in pharmacogenomics: studies in cardiovascular disease and asthma

Abstract

A drug that is effective in one group of patients may have a reduced or no effect in other patients. Similarly, the risk for side effects differs between patients. The discipline of pharmacogenomics studies how genetic variation in the population can influence this drug response. In this thesis, we have used multiple approaches to examine these challenges and opportunities in pharmacogenomics: we studied variants with well-established functional effects, used specialized genotyping chips focusing on cardiovascular genes or rare variation, and increased sample sizes by meta-analyzing studies. Thematically, we have focused on common diseases: atherosclerosis, asthma, and high blood pressure. Chapter 1 of this thesis is the General Introduction. In Chapter 2 we review current evidence for associations between genetic variability and differences in response to statins and ACE-inhibitors. Here, we show that the (initial) enthusiasm for possible applications of pharmacogenetic research has resulted in a high number of publications. Many of these studies, which combine genetics with pharmacology, are of low quality, at least in the field of statin pharmacogenetics. This results in false-positive findings and non-replication. Chapter 3 describes three new studies into the pharmacogenetics of statin response. In all studies, we combined evidence from several independent studies, and explored how the polymorphisms change the response to statins. Results of these studies indicated that there is a small, but statistically significant effect of genetic variation on statin efficacy. Chapter 4 presents candidate gene (array) approaches to asthma and lung function pharmacogenetics. Again, the effects of genetic variation on the response to drugs in this disease area are small. The thesis concludes with the General discussion, which provides a general discussion of the findings in a broader perspective, commenting on the implications for clinical practice, methodological challenges and opportunities, and making recommendations for future research. The ideal of ‘personalized medicine’, where every patient receives a tailored treatment, is difficult to achieve due to the small effect sizes, a generally favorable response, and the added difficulty of a need for genotyping. It therefore seems unlikely that it will become the norm in the coming years, especially for common diseases such as atherosclerosis, diabetes, or asthma. We have also seen that there are still many, yet unused, possibilities to improve the current pharmacogenomic research methods, and to have an impact on medicine. Much of this pharmacogenomic research will aid start-ups and established pharmaceutical companies in establishing targets for pharmacological action. Pharmacogenomics can also help to get market approval for drugs, if there are problems with side effects or a lack of efficacy in a genetically-defined subgroup of patients. We further plead for a larger role for multiethnic research in pharmacogenetic research. With a systematic and hypothesis-free approach we have learned a great deal about human biology and disease in the last decade. It is time to turn this knowledge into new and improved therapies.