Pharmacogenomics of Essential Hypertension: Are We Going the Right Way?

Abstract

Identifying the genetic predictors of the therapeutic response to drugs is the role of pharmacogenomics. Although polymorphisms in several genes have been associated with the blood pressure response to diuretics, beta-blockers and ACE-inhibitors, the pharmacogenomics of essential hypertension is still attempting to find satisfactory scientific evidence to be translated into clinical practice. The main reasons for this apparent failure are: the small sample sizes of the cohorts of patients analyzed, the methodological variability, the complexity of the biological organization, the context-dependency and the genetic heterogeneity. This review will summarize the available data on antihypertensive drugs and the criteria used for study design and conduction, focusing on their strong points and limitations.

Pharmacogenetics of Antihypertensive Treatment: Detailing Disciplinary Dissonance

“…Failure to create realistically complex hypotheses that include genetic, environmental and biological interactions has likely resulted in oversimplified or partial pictures of disease and its response to treatment. Ideal studies should make use of robust microarray technology [15], incorporate haplotype [11,53,54], copy number variation and epigenetic [55] analyses and consider gene by environment interactions beyond that of gene by drug. Researchers should not naively assume that genes that are associated with the development of hypertension and its sequelae are plausible pharmacogenetic candidates [11]; some pharmacodynamic pathways may be distinct from disease and phenotype pathways.…”

“…Ideal studies should make use of robust microarray technology [15], incorporate haplotype [11,53,54], copy number variation and epigenetic [55] analyses and consider gene by environment interactions beyond that of gene by drug. Researchers should not naively assume that genes that are associated with the development of hypertension and its sequelae are plausible pharmacogenetic candidates [11]; some pharmacodynamic pathways may be distinct from disease and phenotype pathways. A priori biological knowledge must always be brought to bear on the design and interpretation of studies, from the inheritance model used in an analysis [50] to the biological plausibility of candidates identified via genome-wide techniques [12].…”

Genome-Wide Association Study Identifies CAMKID Variants Involved in Blood Pressure Response to Losartan: The Sophia Study

“…We think these considerations are indeed a key point in the study design and conduction of a pharmacogenomics study: never treated hypertensives are rather difficult to find and it took several years to assemble our cohort. These considerations are expressed in detail elsewhere [24].…”

Essential Hypertension: Translating Pathophysiology into Pharmacogenomics

“…Nevertheless, as discussed in our recent review, the results originating from pharmacogenomic studies are frequently biased by important methodological flaws in study design, patients' selection, statistics analysis [Filigheddu, 2006], which are summarised in tab.2. To recall, samples of adequate size should be planned a priori, mainly when genes with minor effects are evaluated.…”