Has pharmacogenetics brought us closer to 'personalized medicine' for initial drug treatment of hypertension?
ABSTRACT To describe recent advances in antihypertensive pharmacogenetics and discuss challenges related to translating this knowledge into 'personalized medicine' for the initial drug treatment of hypertension.
Recent studies included both prospective and retrospective analyses ranging from small clinical investigations of 42 participants to large, multicenter, randomized, outcome-based clinical trials of nearly 40 000 individuals. Treatment with drugs from five classes of antihypertensives was evaluated in these studies. The duration of treatment ranged from week-long follow up for blood pressure response to a decade-long follow up for clinical outcomes. In total, associations with 12 different candidate genes were assessed. These studies present the now familiar mixture of significant and nonsignificant pharmacogenetic findings that are sometimes consistent with, sometimes inconsistent with, previous findings in antihypertensive pharmacogenetics.
Recent research in antihypertensive pharmacogenetics has added to the existing evidence base, and novel genes and variants as well as new methodologies are cause for continued optimism. However, translation of genomic science to clinical settings has not kept pace with growing interest in personalized medicine for hypertension. New research paradigms may be needed to translate pharmacogenetics into clinical tools. Clinical application will also require a trained clinical workforce, validated genetic tests, and payers willing to fund pretreatment testing.
- SourceAvailable from: Sandosh Padmanabhan
[Show abstract] [Hide abstract]
- "The association between BP lowering with beta-blockers and genetic polymorphisms in the beta1-adrenergic receptor gene (ADRB1)- Ser49Gly and Arg389Gly, suggest greater BP lowering in the Arg389Arg individuals. The commonly studied is the Arg389Gly polymorphism, for which many, but not all, studies show a significant association with antihypertensive response to beta-blockers and two independent studies have suggested an association between treatment related hypertensive outcomes and ADRB1 SNPs [38,39,40]. There is some evidence that the Ser49Gly polymorphism alone does not importantly influence BP response, but when considered in combination with the Arg389Gly polymorphism, it may be more informative than Arg389Gly alone [41,42]. "
ABSTRACT: Hypertension is a major public health problem, but measures to reduce blood pressure and thus cardiovascular risk are complicated by the high prevalence of treatment resistance, despite the availability of multiple drugs. Drug side-effects contribute considerably to suboptimal blood pressure control. Clinicians must often rely on empirical methods to match patients with effective drug treatment. Hypertension pharmacogenomics seeks to find genetic predictors of response to drugs that lower blood pressure and to translate this knowledge into clinical practice. In this review we summarise the current status of hypertension pharmacogenetics from monogenic hypertension to essential hypertension and discuss the issues that need to be considered in a hypertension pharmacogenomic study.Pharmaceuticals 06/2010; 3(6):1779-1791. DOI:10.3390/ph3061779
- [Show abstract] [Hide abstract]
ABSTRACT: Cytochrome P450 1A2 metabolizes a wide range of therapeutic drugs, including several used to treat diseases common in sub-Saharan Africa. Variation in the gene (CYP1A2) has been reported to be associated with differential efficacy of therapeutic drugs and adverse drug reactions. To gain a better understanding of the extent of variation in the coding and exonflanking non-coding regions of CYP1A2, 762 chromosomes from members of five ethnic groups (Afar, Amhara, Anuak, Maale and Oromo) distributed in a rough north east to south west transect across Ethiopia were re-sequenced. Substantial variation was observed, much of which was novel. As a consequence, a diagnostic test based on previously known variation cannot predict functional variation in Ethiopians. Evidence of purifying selection acting on CYP1A2 was found and coalescent date estimates of CYP1A2 variants were old, with many pre-dating expansions of anatomically modern human out of Africa. Variants within the transcription factor 7-like 2 gene (TCF7L2), which are associated with an increased risk of type 2 diabetes (T2D), were common in multiple Ethiopian populations. TCF7L2 haplotype distribution varied among groups suggesting that T2D susceptibility may also vary, with most groups likely having a West African TCF7L2 risk for the disease and some having more of a European TCF7L2 risk. Many CYP1A2 and TCF7L2 haplotypes can be of important predictive value in the planning and provision of healthcare. These findings are not only of benefit to native Ethiopians, but are also of increasing importance in the planning of healthcare intervention in the developed world, where growing numbers of individuals with recent Ethiopian descent are living. Comparing data with those from publicly available databases it appears that Ethiopian groups display a very high level of diversity that includes most of the common variation observed elsewhere.
- [Show abstract] [Hide abstract]
ABSTRACT: In the United States, only about one third of hypertensive individuals successfully control their blood pressure. One reason for this is the unpredictable response individuals have to treatment. Clinicians often rely on empirical methods to match patients with effective treatment. Hypertension pharmacogenetics seeks to find genetic predictors of response to drugs that reduce blood pressure or unfavorable cardiovascular outcomes. For more than a decade, investigators have been assessing associations between genetic polymorphisms and response to antihypertensive drugs. This article reviews 29 studies published since 2008. Although inconsistent findings remain common, trends are emerging for several gene-treatment combinations. Nevertheless, researchers continue to cite differences in study design, variable methods for assessing pharmacologic exposures, and small sample sizes as explanations for these inconsistencies. Assuming that common genetic variation plays a role in response to antihypertensive drugs, disciplinary progress hinges on our ability to launch large studies using high-fidelity phenotyping with multiple drugs and ethnic groups.Current Cardiovascular Risk Reports 11/2009; 3(6):441-451. DOI:10.1007/s12170-009-0065-0