Pharmacogenomic approaches to study the effects of antihypertensive drugs

Abstract

Pharmacogenomic studies aim to clarify the role of various genes and their variations in relation to the effects of antihypertensive drugs to establish a personalized pharmacotherapeutic treatment based on a patient's genetic background. Until recently, there have been numerous pharmacogenetic/pharmacogenomic studies on antihypertensive drugs using candidate genes, but only a few genome-wide approaches have been completed. In this review article, we discuss current trends and future directions of pharmacogenomic studies on antihypertensive drugs. Hypertension Research (2012) 35, 796-799; doi:10.1038/hr.2012; published online 28 June 2012 Keywords: antihypertensive drugs; candidate genes; GWAS; pharmacogenomics; tailored medicine INTRODUCTION Hypertension is the most common risk factor for atherosclerotic cardiovascular diseases, and its morbidity is greater than 50% in subjects aged 65 years and older in Japan and most Western countries. In Japan, the number of patients with hypertension is estimated to be greater than 40 million. 1 Hypertension is a multifactorial disease in which genetic and environmental factors are closely related. Specifically, genetic factors can influence blood pressure elevation by 30-50%. 2 Thus, over the last decade, many genetic studies have aimed to clarify the causal genes of hypertension, as reviewed previously. 3 Genetic research on hypertension started using the candidate gene approach by investigating renin-angiotensin system (RAS)-related genes. [4][5][6] Recently, several large-scale genome-wide association studies (GWASs) for hypertension 7-9 were performed, and B50 single nucleotide polymorphisms (SNPs) were identified as possible causal genes.The goal of genetic studies on hypertension is mainly to clarify the causal genes of hypertension and the mechanisms of blood pressure elevation. Consequently, these approaches may lead to the production of novel antihypertensive drugs. Another important aim is to establish personalized pharmacotherapy based on genetic information. These were the two main aims of the Japanese Millennium Project for Hypertension. 10 As mentioned, the first aim may be reasonably addressed by large-scale GWAS, but the second aim has not yet been examined in the field of hypertension research.Recent studies indicate that the heterogeneity of patients' responses to antihypertensive treatment is, at least in part, genetically determined. 11 This finding underscores the role of pharmacogenetic/ pharmacogenomic research in identifying either functional genetic variations or those variations inherited by linkage disequili-

<p>Pharmacogenomics And Hypertension: Current Insights</p>

“…In order to identify potential genetic predictors of antihypertensive responses, two main approaches have been applied: a hypothesis-driven approach on the candidate genes, encoding proteins involved in signaling pathways affected by antihypertensive drugs, and an unbiased hypothesis-free approach with genome-wide association studies (GWAS), supported by the randomness basis of frequentist statistics 12,13. During the past decade, GWAS have overcome the application of candidate gene approach, resulting in the identification of several previously unknown candidate loci or genes, but the advantages and limitations of this method in hypertension pharmacogenomics compared to the hypothesis-driven approach are still under debate 13.…”

Screening and validation of double allele-specific binding F-primers for the measurement of antihypertensive pharmacogenomics

“…Metabolizing most ARBs, CYP2C9 is a member of the cytochrome P450 oxidase superfamily ( 12 ). Patients with the CYP2C9 * 3 ( * 1/ * 1) allele extend their fast metabolic response to ARBs ( 13 , 14 ).…”

Human Pharmacogenomic Variation of Antihypertensive Drugs: From Population Genetics to Personalized Medicine

“…Unfortunately, although hypertension pharmacogenetic data promises to play an important role in patient management, this information is not yet ready to be transferred from the bench to the bed side. Indeed, several confounding factors are present in the correlation between genotype (i.e., genomic background) and phenotype (i.e., response to antihypertensive drugs), such as environment and epigenetics [10]. This leads us to believe that multiple rare variants deter mine a great portion of the complex phenotype predisposition, shifting the attention from common genetic variants to rare ones [11].…”

“…To date, most of the hyperten sion pharmaco genomic studies conducted have been genecandidate investigations or genome wide association studies [10]. These approaches are not suitable for identifying rare variants, as they likely result in missing heritability in the genetic predisposition to antihypertensive drug response.…”