The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with β-blockade

1MCRI Center for Translational Genomics, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA.
Journal of Human Hypertension (Impact Factor: 2.7). 04/2008; 22(7):512-515. DOI: 10.1038/jhh.2008.23


Journal of Human Hypertension is exclusively concerned with all clinical aspects of human hypertension. The journal publishes fully refereed original research papers from around the world.

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Available from: Jose M Ordovas, Feb 27, 2014
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    • "The importance of BK- 1 subunits in the regulation of vascular physiology is underscored by the  1 subunit knockout mice, in which Ca 2+ sparks are uncoupled to BK channels in the vascular smooth muscle cells, and these animals are hypertensive (Brenner et al., 2000; Pluger et al., 2000). In addition, there is a compensatory increase in vascular BK-β 1 expression in spontaneously hypertensive rats (Chang et al., 2006), while a gain-of-function mutation in BK-β 1 (E65K) is associated with low prevalence of diastolic hypertension in humans (Fernandez-Fernandez et al., 2004; Kelley-Hedgepeth et al., 2008; Nielsen et al., 2008) and with reduced risk of myocardial infarction and stroke, particularly in elderly women (Senti et al., 2005). BK channels maintain smooth muscle cell Ca 2+ homeostasis and regulate vascular tone through a negative feedback mechanism. "

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    • "(Heart SCORE) is a single-site prospective community-based cohort study investigating the mechanisms underlying population disparities in cardiovascular disease (Aiyer et al., 2007; Kelley-Hedgepeth et al., 2008). Our sample includes 1191 subjects (425 African Americans and 766 white persons) who provided consent and a DNA sample. "
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    ABSTRACT: The μ-opioid receptor (MOR) plays an important role in modulating analgesia, feeding behavior, and a range of autonomic functions. In the current study, we investigated the degree to which 13 naturally occurring missense mutations affect the pharmacological properties of the human MOR. After expression of each receptor in human embryonic kidney 293 cells, signaling (Gα(i/o)-mediated) induced by peptide agonists was assessed using luciferase reporter gene assays. Multiple mutants (S66F, S147C, R260H, R265C, R265H, and S268P) show a significant reduction in agonist potency. At the N190K variant, agonist-mediated signaling was essentially absent. Enzyme-linked immunosorbent assay, microscopic analysis, and radioligand binding assays revealed that this mutant shows markedly reduced cell-surface expression, whereas all other receptor variants were expressed at normal levels. Surface expression of the N190K variant could be increased by incubation with the alkaloid agonist buprenorphine or with either naltrexone or naloxone, structurally related MOR antagonists. We were surprised to find that both putative antagonists, despite being inactive at the wild-type MOR, triggered a concentration-dependent increase in N190K receptor-mediated signaling. In contrast, peptidic ligands failed to promote expression or rescue function of the N190K mutant. Subsequent analysis of the N190K variant in an ethnically diverse cohort identified this isoform in a subgroup of African Americans. Taken together, our studies reveal that the N190K mutation leads to severe functional alterations and, in parallel, changes the response to established MOR ligands. The extent to which this mutation results in physiological abnormalities or affects drug sensitivity in selected populations (e.g., those with chronic pain or addiction) remains to be investigated.
    Preview · Article · Nov 2010 · Molecular pharmacology
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    • "This supports the polygenic nature of antihypertensive response and highlights the challenges to dissect this trait. Another potential candidate gene is KCNMB1, for which SNPs have been associated with BP response in three independent populations, and treatment-related outcomes in one [48,49]. "
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    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.
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