Cardiovascular pharmacogenetics

Abstract

Human genetic variation in the form of single nucleotide polymorphisms as well as more complex structural variations such as insertions, deletions and copy number variants, is partially responsible for the clinical variation seen in response to pharmacotherapeutic drugs. This affects the likelihood of experiencing adverse drug reactions and also of achieving therapeutic success. In this paper, we review key studies in cardiovascular pharmacogenetics that reveal genetic variations underlying the outcomes of drug treatment in cardiovascular disease. Examples of genetic associations with drug efficacy and toxicity are described, including the roles of genetic variability in pharmacokinetics (drug metabolising enzymes) and pharmacodynamics (e.g. drug targets). These findings have functional implications that could lead to the development of genetic tests aimed at minimising drug toxicity and optimizing drug efficacy in cardiovascular medicine.

Priority pharmacogenetics for the African continent: focus on CYP450

“…Altered drug response in the management of cardiovascular disease is related to variability in the pharmacogenetic make-up of a patient [39]. In this context, CYP2C9 is probably the best described enzyme with pharmacogenetic implications.…”

Evidence for Clinical Implementation of Pharmacogenomics in Cardiac Drugs

“…For example, the response rate to any given hypertension medication is approximately 50%, regardless of the class of medication 4,8 . In general, drugs are developed based on their effectiveness in large, carefully selected populations; a drug’s performance in that setting is less informative when treating individual patients 5,9 . Thus, there is a need to better identify therapies that are both more likely to be beneficial and less likely to cause harm to individual patients, who show remarkable variability in their response to medications 10,11 .…”

“…Pharmacogenomics, the study of genetic variation in drug response, has enabled the identification of genetic variants that impact response or toxicity to several prominent cardiovascular drugs 5,9,12–16 . While the effective clinical translation of this information has the potential to guide the selection and dosing of medications 4,17 few cardiovascular drug pharmacogenomic findings have been translated into clinical practice 18,19 .…”

Evaluation of Predictive Cyp2C19 Genotyping Assays Relative to Measured Phenotype in a South African Cohort

“…Since it is recognized that sub-optimal therapies are prevalent in developing countries such as South Africa, pharmacogenetics could have a positive impact. 3 Genetic variation in CYP2C19 (OMIM 124020) has been associated with variable responses to numerous drugs including clopidogrel (anticoagulant), citalopram (and many other antidepressants), proguanil (prophylactic anti-malarial) and omeprazole (and other proton pump inhibitors) [6][7][8][9][10][11][12] The non-functional CYP2C19*2 and *3 alleles are the most commonly genotyped and have been prioritised in many CYP2C19 studies [13]. Responsible for increased CYP2C19 expression, CYP2C19*17 is important for the prediction of UMs and has been found to be relatively frequent in certain populations [14][15][16][17][18][19].…”