Role of the Gly460Trp polymorphism of the α-adducin gene in primary hypertension in Scandinavians

Melander, Olle; Bengtsson, Kristina; Orho‐Melander, Marju; Lindblad, Ulf; Forsblom, Carol; Råstam, Lennart; Groop, Leif; Hulthén, U L

doi:10.1038/sj.jhh.1000942

Cited by 32 publications

(24 citation statements)

References 24 publications

(30 reference statements)

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“…They found evidence that ␣-adducin gene polymorphism is associated with some cases of essential hypertension in man, with plasma renin activity being lower in the predisposed subjects. 209 The findings have been supported by some, 211,212 but not all, [213][214][215][216] other workers.…”

Section: Genetic Aspectssupporting

confidence: 71%

The renin-angiotensin system in the year 2000

Nicholls

Robertson

2000

J Hum Hypertens

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Section: Genetic Aspectssupporting

confidence: 71%

The renin-angiotensin system in the year 2000

Nicholls

Robertson

2000

J Hum Hypertens

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“…In 10 populations, a positive association was found (10,13,32,42,80,116,119,124,156), whereas in two populations, a positive association was found only in women (128) or young subjects (132). In 13 populations, no association was present (2,3,38,70,74,79,84,88,100,116,119,124,151). In three studies (116,119,124), both positive and negative associations are observed in different populations.…”

Section: Studies In Humansmentioning

confidence: 86%

Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Bianchi

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Bianchi, Giuseppe. Genetic variations of tubular sodium reabsorption leading to "primary" hypertension: from gene polymorphism to clinical symptoms. Am J Physiol Regul Integr Comp Physiol 289: R1536-R1549, 2005. doi:10.1152/ajpregu.00441.2005.-The definition of the most appropriate strategy to demonstrate causation of a given geneticmolecular mechanism in a complex multifactorial polygenic disease like hypertension is hampered by the underestimation of the complexity arising from the genetic and environmental interactions. To disentangle this complexity, we developed a strategy based on six steps: 1) isolation of a rodent model of hypertension (Milan hypertensive strain and Milan normotensive strain) that shares some pathophysiological abnormalities with human primary hypertension; 2) definition in the model of the sequence of events linking these abnormalities to a genetic molecular mechanism; 3) determination of the polymorphism of the three adducin genes discovered in the model both in rats and in humans; 4) comparison at biochemical and physiological levels between the rodent models and the hypertensive carriers of the "mutated" gene variants; 5) evaluation of the impact of the adducin genes in hypertension and its organ complications with association and linkage studies in humans, also considering the genetic and environmental interactions; and 6) development of a pharmacogenomic approach aimed at establishing the therapeutic benefit of a drug interfering with the sequence of events triggered by adducin and their effect's size. The bulk of data obtained demonstrates the importance of a multidisciplinary approach considering a variety of genetic and environmental interactions. Adducin functions within the cells as a heterodimer composed of a combination of three subunits. Each of these subunits is coded by genes mapping to different chromosomes. Therefore, the interaction among these genes, taken together with the interactions with other modulatory genes or with the environment, is indispensable to establish the adducin clinical impact. The hypothesis that adducin polymorphism favors the development of hypertension via an increased tubular sodium reabsorption is well supported by a series of consistent experimental and clinical data. Many mechanistic aspects, underlying the link between these genes and clinical symptoms, need to be clarified. The clinical effect size of adducin must be established also with the contribution of pharmacogenomics with a drug that selectively interferes with the sequence of events triggered by the mutated adducin.genes; blood pressure; Na-K pump; Na channel; adducin The difficulty lies, not only in the new ideas, but in escaping the old ones. J. M. Keynes STARLING'S LONG-LASTING concern was to use physiology as a means to bring basic science to the bedside. Indeed, by integrating the capillary fluid exchange with the cardiac pump function, Starling provided a substantial contribution to bridge the gap between the contemporary basic science of circulation and the clinical sympto...

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“…20 Two subjects from the previous study 20 were excluded because of unsuccessful genotyping. Briefly, the patients with primary hypertension were diagnosed before the age of 60 years and were all receiving chronic pharmacological antihypertensive treatment.…”

Section: Subjects and Phenotypingmentioning

confidence: 99%

Genetic Variants of Thiazide-Sensitive NaCl-Cotransporter in Gitelman’s Syndrome and Primary Hypertension

et al. 2000

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Abstract-Gitelman's syndrome is an autosomal recessive disorder characterized by electrolyte disturbances and low blood pressure. The disease is caused by homozygous or compound heterozygous inactivating mutations in the thiazidesensitive NaCl-cotransporter gene leading to reduced renal sodium reabsorption. We report 4 patients with Gitelman's syndrome from southern Sweden, all in whom we identified compound heterozygous mutations in the thiazide-sensitive NaCl-cotransporter gene (Gly439Ser, Gly731Arg, Gly741Arg, Thr304Pro, and 2745insAGCA), of which the latter 2 have not been described before. We hypothesized that such mutations in their heterozygous form protect against primary hypertension in the general population and that the gene may also harbor activating mutations that increase the risk for primary hypertension. Accordingly, the gene was screened for mutations in 20 patients with primary hypertension and in 20 normotensive subjects by single-strand conformation polymorphism and direct DNA sequencing. The Arg904Gln, Gly264Ala, and C1420T variants, found in the mutation screening of subjects without Gitelman's syndrome, were studied further. Population genotype frequencies were determined in 292 unrelated patients with primary hypertension and 264 unrelated normotensive subjects from southern Sweden. Gln904 homozygotes were overrepresented in hypertensive patients compared with normotensive subjects (5 of 292 versus 0 of 264; Pϭ0.03). In conclusion, we confirm that Gitelman's syndrome is caused by mutations in the thiazide-sensitive NaCl-cotransporter gene. Our results further suggest that subjects homozygous for the Gln904 variant have an increased risk for development of primary hypertension. (Hypertension. 2000;36:389-394.)

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Role of the Gly460Trp polymorphism of the α-adducin gene in primary hypertension in Scandinavians

Cited by 32 publications

References 24 publications

The renin-angiotensin system in the year 2000

The renin-angiotensin system in the year 2000

Genetic variations of tubular sodium reabsorption leading to “primary” hypertension: from gene polymorphism to clinical symptoms

Genetic Variants of Thiazide-Sensitive NaCl-Cotransporter in Gitelman’s Syndrome and Primary Hypertension

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