Clinical Utility of Pharmacogenetic Biomarkers in Cardiovascular Therapeutics: a Challenge for Clinical Implementation

Abstract

In the past decade, significant strides have been made in the area of cardiovascular pharmacogenomic research, with the discovery of associations between certain genotypes and drug-response phenotypes. While the motivations for personalized and predictive medicine are promising for patient care and support a model of health system efficiency, the implementation of pharmacogenomics for cardiovascular therapeutics on a population scale faces substantial challenges. The greatest obstacle to clinical implementation of cardiovascular pharmacogenetics may be the lack of both reproducibility and agreement about the validity and utility of the findings. In this review, we present the scientific evidence in the literature for diagnostic variants for the US FDA-labeled cardiovascular therapies, namely CYP2C19 and clopidogrel, CYP2C9/VKORC1 and warfarin, and CYP2D6/ADRB1 and β-blockers. We also discuss the effect of HMGCR/LDLR in decreasing the effectiveness of low-density lipoprotein cholesterol with statin therapy, the SLCO1B1 genotype and simvastatin myotoxicity, and ADRB1/ADD1 for antihypertensive response.

Opinions, hopes and concerns regarding pharmacogenomics: a comparison of healthy individuals, heart failure patients and heart transplant recipients

“…Thus it is essential to assess the public's perceptions concerning pharmacogenomic testing and its potential uses. [2][3][4] Previous studies with a similar purpose have been conducted both in the general public [5][6][7][8][9][10] and in patients suffering from chronic medical conditions. [11][12][13][14] These investigations have revealed varying degrees of interest towards pharmacogenomics, but none have provided a direct comparison of attitudes between healthy individuals and patients with chronic diseases.…”

“…Furthermore, no study has evaluated the attitudes of patients with advanced cardiac disease or having received cardiac transplantation. Given the many recent publications highlighting the fact that genetic information could be useful to optimize heart failure (HF) 4,15,16 and transplant patients' pharmacotherapy, [17][18][19] we have designed a project with the aim of comparing the opinions, hopes and concerns regarding pharmacogenomics among healthy volunteers, patients with HF and heart transplant recipients. As personal health-related experiences such as previous use of medical tests or history of side effects have a positive impact on the general public's attitudes towards pharmacogenomics, 6,7,13,20 we hypothesized that HF and heart transplant patients would be more willing to undergo pharmacogenomic testing than healthy individuals.…”

Genetic Engineering: Tinkering with the Human Body

“…This gene must function properly to convert clopidogrel to an active product ("metabolite") before it can do its job. Having even just one "defective" copy of that gene (being heterozygous for the CYP2C19*2 allele) has been associated with an increased risk of blood clots forming in stents and elsewhere [73,74]. However, because no large clinical trials have confirmed the exact level of this risk, current FDA recommendations advise that alternative therapy be used for individuals homozygous for that particular allele, but they also do not require genetic testing to assess this.…”

“…One rare but potentially serious side effect of statins is breakdown of muscle, "rhabdomyolysis." Patients who are homozygous or heterozygous for a variant of the SLCO1B1 gene were found in one study to have a 16.9-and 4.5-fold increase, respectively, in this side effect with high doses of statin therapy compared to those did not have that allele [73,74]. Groups of multiple genes associated with specific conditions, such as the risk of develop-ing cardiovascular disease or to assess rejection after a heart transplant, can also be tested, although their overall clinical value is still being assessed [58].…”

Cardiovascular Drug Discovery: A Perspective from a Research-Based Pharmaceutical Company

“…The genome-wide association studies arising from the international human Hapnap project reveal a startling degree of structural genomic variation, which, although of fundamental scientific importance, are unlikely to lead to the identification of genetic causes of common cardiovascular conditions (Hardy and Singleton 2009). In a recent critical evaluation of pharmacogenetic biomarkers in cardiovascular therapeutics, Ong et al (2012) concluded that "the greatest obstacle to clinical implementation of cardiovascular pharmacogenetics may be the lack of both reproducibility and agreement about the validity and utility of the findings. "…”