Gene-drug interactions that could help to tailor treatment for people with high blood pressure have been identified in a statistical analysis of siblings participating in a US study of genetic factors that influence blood pressure and the development of hypertensive complications.
As the researchers led by Sharon Kardia from the Department of Epidemiology at the University of Michigan note, fewer than half of treated hypertensives have their blood pressure adequately controlled, despite the broad variety and efficacy of antihypertensive drugs.
It is well known, they report in the online open access journal BMC Medical Genetics, that people with high blood pressure respond heterogeneously to antihypertensive therapies, often requiring multiple medication to get their blood pressure down. Therefore, identifying genetic variations that influence the biochemical, physiological and anatomical mechanisms regulating blood pressure response to antihypertensives “could have a major public health impact on reducing the target organ damage due to hypertension by targeting drug interventions based on an individual’s biological profile”, the researchers suggest.
They pursued this goal by testing for evidence of gene-by-drug interactions in a population sample of non-Hispanic white hypertensives from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Part of the US National Heart Lung and Blood Institute’s Family Blood Pressure Program, the GENOA study recruited, among others, 575 sibships (the total number of children born to one set of parents) from Rochester, Minnesota who had at least two hypertensive siblings diagnosed before they reached 60 years of age.
Linkage analysis of the sibships identified a region on chromosome 2 that was investigated using 70 single nucleotide polymorphisms (SNPs) typed in seven positional candidate genes, including adducin 2 (ADD2). This particular gene was the focus of the analysis reported in BMC Medical Genetics, which examined whether SNPs in ADD2 influenced blood pressure levels in hypertensives stratified by category of drug therapy.
To reduce the risk false positives, the researchers used cross-validation methods that involved estimating a model for predicting blood pressure levels in one subgroup and testing it on individuals outside the study group.
They found that eight SNPs in the ADD2 gene were significantly associated with systolic blood pressure in untreated hypertensives. The study also identified SNPs associated with gene-by-drug interactions affecting systolic blood pressure in hypertensives who were on drug therapy. Three SNPs were associated with differential blood pressure responses in beta-blocker users versus hypertensives on diuretics, while two other SNPs were associated with differential responses in people taking renin-angiotensin-aldosterone system (RAAS) inhibitors versus those on diuretics.
There was initial evidence that the effects of genetic variation on blood pressure in people with untreated hypertension might be very different from its effects on hypertensives taking drug therapy.
These results “suggest that ADD2 variation may influence blood pressure responses to specific antihypertensive drug therapies and measurement of genetic variation may assist in identifying subgroups of hypertensive patients who will benefit most from particular antihypertensive drug therapies”, Kardia et al concluded.
Given that blood pressure levels were mediated by a network of multiple factors (physiological, biochemical, genetic and environmental), they added, interactions among these factors were likely to play a major role in determining an individual’s blood pressure or response to antihypertensives. “Further studies in larger clinically representative cohorts are needed to investigate these higher order interactions,” the researchers suggested.