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Journal of Hypertension:
doi: 10.1097/HJH.0b013e328312c0fa
Editorial commentaries

Sluggish genes and hypertension

Jordan, Jens

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Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany

Correspondence to Jens Jordan, MD, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany E-mail:

The notion that blood pressure (BP) is inherited and that genetic variation may predispose to arterial BP is not new. Twin studies suggest that approximately 30–40% of the variability in BP is explained by genetic variance. Moreover, genetic factors also convey risk associated with arterial hypertension. If you have the ‘wrong’ genes you may experience more complications at a given BP level, compared with the ‘right’ genes. The recognition of the important effect of genes on BP and hypertension-associated target organ damage created much enthusiasm among hypertension researchers and funding agencies. The idea was that genetic technology could identify the individual hypertension-producing mechanisms in each patient and that this information could be applied therapeutically. Indeed, in rare patients with monogenic or Mendelian forms of arterial hypertension, a single molecular abnormality increases BP profoundly [1–3]. However, in most patients, multiple genes contribute to the hypertension such that each individual gene has a rather modest effect on BP. Two articles in this issue of the Journal of Hypertension suggest that these genes may include KCNMA1 [4] and KCNMB1 [5]. KCNMA1 encodes the pore forming α subunit, whereas KCNMB1 encodes the regulatory β-1 subunit of the large-conductance Ca2+-dependent K+ (BK) channel.

A Ca2+-dependent K+ channel was first cloned in fruit flies (Drosophila melanogaster). Mutations of the gene cause the ‘slowpoke’ phenotype [6]. Slowpoke is a mildly insulting term for a person that moves slowly. Cartoon aficionados may know that slowpoke Rodriguez, Mexico's slowest mouse, is Speedy Gonzales' cousin. True to their name, slowpoke flies refuse to fly or fly in small hops illustrating the important role of Ca2+-dependent K+ channels in the regulation of neuronal and muscular excitation. The human homologue of the Drosophila slowpoke gene, the KCNMA1 gene, was described in 1994 [7]. The BK channel is composed of four α subunits and four regulatory β subunits. Four different β subunits have been described, namely the β-1, β-2, β-3 and β-4 subunits. The β subunits are encoded by different genes and are expressed in a tissue-specific fashion. The β-1 subunit is primarily expressed in vascular smooth muscle cells. The BK channel appears to serve as negative feedback regulators of vascular tone. The channel responds to membrane depolarization and local increases in intracellular Ca2+-concentration with transient outward K+ currents, thus, attenuating vascular tone.

Mice with genetic β-1 subunit deletion feature an approximately 13 mmHg greater BP than wild type animals [8]. Mice with α-subunit deletion show a ‘slowpoke-like’ reduction in locomotor activity. However, at a given locomotor activity, BP is increased by approximately 6 mmHg in α-subunit knockout animals [9]. The β-1 subunit is downregulated in retinal vessels of diabetic rats [10] and in vascular smooth muscle cells of hypertensive rats [11] The downregulation may be mediated in part through angiotensin II-induced activation of calcineurin and nuclear factor of activated T cells cytoplasmic isoform c3 (NFATc3) [12]. Together, these observations suggest that BK channels are important in the regulation of vascular tone and that BK channel dysfunction could contribute to arterial hypertension. Therefore, α-1-subunit and β-1-subunit genes have been a logical target for genetic studies.

Earlier association studies [13] suggested that polymorphisms in the β-1-subunit gene might affect human baroreflex regulation though an unknown mechanism. In a subsequent study [14,15], a gain of function mutation of the β-1 subunit gene with a glutamic acid to lysine exchange in position 65 (Glu65Lys) was associated with reduced risk for moderate-to-severe arterial hypertension. Remarkably, over a 5-year follow-up period, patients with the gain of function mutation had an odds ratio of 0.11 (95% confidence interval 0.01–0.79) to experience either myocardial infarction (MI) or stroke [15]. A Chinese study [16] also suggested association between variability in the gene and BP. Genetic variation in the gene encoding the BK β-1 subunit may also interact with antihypertensive therapy [17,18]. Yet, a population-based study [19] in Japan did not reproduce the relationship between the Glu65Lys polymorphism and arterial hypertension. Moreover, a family-based association study [20] in Spain failed to detect any association between this polymorphism and ischaemic heart disease. The study by Nielsen et al. [5] in this issue adds an additional layer of complexity. The authors genotyped the KCNMB1 gene in 5729 middle-aged Danes who had participated in a nonpharmacological intervention study for the prevention of ischaemic heart disease. They did not observe a relationship between the Glu65Lys polymorphism and BP in women. In men, each copy of the Lys allele lowered systolic BP by 1.3% and diastolic BP by 1.1%. Even larger studies may be required to reconcile these conflicting results. Clearly, two copies of the lysine allele lower BP much less than any currently available antihypertensive medication.

In this issue, Tomás et al. present data from an association study on the BK α-subunit gene (KCNMA1) and hypertension. The authors sequenced the KCNMA1 gene in a smaller group of normotensive and hypertensive individuals to identify genetic polymorphisms. Of those, two were selected for further analysis because they occurred in at least one participant, namely the IVS17+37T>C and the C864T polymorphism. Then, the authors determined these polymorphisms in 4786 participants from a population-based study in Northern Spain. Genotype frequencies were almost identical in individuals with and without arterial hypertension. Furthermore, neither polymorphism was significantly associated with systolic or diastolic BP. However, the IVS17+37T>C polymorphism was more common in patients with severe systolic arterial hypertension. Participants with two copies of the T allele showed a 3 mmHg lower systolic BP compared with participants with two C copies. The authors also conducted a case–control analysis including 1419 patients with a first MI. The analysis suggested that genetic variability in the KCNMA1 gene might be weakly associated with MI risk.

At this point, it is unknown how the two polymorphisms studied by Tomás et al. could affect BP. The C864T polymorphism does not lead to an amino acid exchange. Furthermore, the IVS17+37T>C polymorphism is located in an intronic region. The authors excluded the possibility that the polymorphism produces different splice variants of the α subunit. Finally, the authors did not observe an effect of the polymorphism on α-subunit expression. Therefore, they speculated that the polymorphism might be inherited together with another hitherto fore unknown genetic KCNMA1 variant affecting BP control.

The ultimate goal of medical research including large-scale genetic studies is to improve patient care. Once we know all the genes contributing to arterial hypertension, will this change clinical practice? In the year 2008, we do not know all the genes causing arterial hypertension in patients. We do not even know the genetic mechanisms causing arterial hypertension in most of our favourite animal models. Therefore, it is difficult to predict what might happen when the information is in. We may learn some lessons from other cardiovascular risk factors that have been worked up genetically, such as low-density and high-density cholesterol levels. Similarly to arterial hypertension, cholesterol levels are affected by many genes. Another similarity between arterial hypertension and lipid disorders is that the proportion of patients in which the risk factor is inherited in a monogenic fashion is relatively small. Yet, most of the genes contributing to variability in cholesterol levels are known [21]. So far, this information has not changed clinical practice. In recent years and decades, we have spent a fortune to work up hypertension-inducing genetic mechanisms. Drugs, for the most part, already occupy the Mendelian syndrome targets. Hopefully, the investment will ultimately result in better medicines for our patients; however, thus far the results from the genetic investments are not encouraging. The BK channel might be a suitable treatment target and prove to be an exception in that regard.

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