From Pharmacogenetics to Gene Expression: Implications for Precision Medicine in Diabetes

Abstract

Approximately 25–60% of patients show specific pharmacological responses to a particular drug. We call this interindividual variability (IV) response to drugs affecting their efficacy and the appearance of side effects in individuals. This IV may be due to multifactorial components such as genetic factors (single nucleotide polymorphisms, SNPs; and copy number variations, CNV), environmental stimuli, epigenetic modulation, disease/health conditions, or drug interactions, among others. Therefore, these factors can influence the response to the drug by modifying absorption, metabolism, pharmacokinetics (PK), and pharmacodynamics (PD), causing the loss of treatment efficacy or leading to adverse drug reactions with negative consequences for patients. The knowledge in pharmacogenetics (study of pharmacological consequences of single gene mutations) and pharmacogenomics (study of the influence of many gene or gene patterns in the reponse to drugs), disciplines that seek to predict how a specific individual responds to the administration of a particular drug, has advanced by leaps and bounds thanks to “omics” technologies. Nonetheless, despite, the development of next-generation sequencing platforms and the mapping of the human genome have transformed the field of pharmacogenetics, the translational into clinical practice has been slow. Therefore, identification of SNPs that could affect the expression of pharmacogenes in order to make associations with PK and PD will improve our understanding of genetic effects on drug efficacy and transfer it to the clinic. Type 2 diabetes (T2D) represents a national public health problem, not only because of the high frequency of the disease reported worldwide, but also because of the poor adherence to therapeutic management, whose causes have not yet been clarified. One of the challenges in the management of diseases to reach optimal treatment is the complex genetic background. Hence, the integration of multiple levels of pharmacological information, including variation in gene sequence, impact in drug response, and function of drug targets, could help us to predict sources of interpatient variability in drug effects, laying the basis for precision therapy. Thus, the present chapter aims to collect all the available data about genetic variations in pharmacogenes affecting drug response in T2D and integrate it with their effect on gene expression to elucidate their impact in pharmacological efficacy.