Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Default user image.

Jonas Dahlberg

Physician

Default user image.

Genetic predisposition to salt sensitivity and cardiovascular disease

Author

  • Jonas Dahlberg

Summary, in English

Abstract

The average amount of salt ingested is about 10 grams daily compared to less than one gram in pre-historic life. Salt, althought somewhat debated, is considered a risk factor for elevated blood pressure and end organ damage beyond the blood pressure effect. Thus, salt contributes to the hypertensive phenotype, increase risk of cardiovasvcular disease, deaths and is a great socioeconomic burden. An individual´s blood pressure reaction to a given amount of salt defines a person’s degree of salt senistivity. Interestingly, most monogenic hypertensive disorders concerns renal salt handling in the distal nephron. For example, in Liddle’s syndrome an intracellular subunit of the amiloride sensitive sodium channel (ENaC) is mutated making it insensitive to down regulation by the ubiquinating protein NEDD4L. This leads to increased ENaC density in the apical membrane in tubuli cells and Liddle’s syndrom is characterised by a severe salt senistive hypertension but can be successfully treated with salt restriction or amiloride. Furthermore, in response to aldosteron SGK-1 is up-regulated and in turn SGK-1 phosphorylates NEDD4L which inhibits the ubiquitination ability of NEDD4L leading to increase in ENaC, salt reabsorption and whater load.

In this thesis we postulated that genetic variance of NEDD4L and SGK-1could mimic Liddle’s syndrome but with a clinically less severe phenotype. In the first paper we found that the functional and previuosly blood pressure associated combination of two NEDD4L polymorphisms were significantly associated with salt sensitivity and low levels of plasma renin. In the second paper we followed up these findings and related the salt sensitive associated genotype combination with marginally higher blood pressure at base line, increasd risk of cardiovascular disease and death in a large prospective population study. In the third paper we investigated two polymorphisms in SGK-1 that previously have been associated with base line and longitudinal blood pressure elevation and found that genetic variance of SGK-1 were associated with ischemic stroke in two independent cohorts from south of Sweden. In paper number four we we followed up the two blood pressure and ischemic stroke associated polymorphisms and additionally genotyped all tag-SNPs of the SGK-1 locus and related it to myocardial infarction in two indepenent populations. We found nominally significant associations between the SGK-1 locus and myocardial infarction but we could not reproduce these findings in a replication cohort.

Thus, we conclude that genetic variance in the aldosterone driven SGK-1 – NEDD4L axis in the distal nephron is associated with salt sensitivity, CVD and ischemic stroke. Interestingly the associations in paper two and three were at least partially blood pressure independent which may indicate that any other proteins or physiological processes are regulated by SGK-1/ NEDD4L leading to end organ damage beyond the effect of blood pressure.

Department/s

  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2014

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

2014:74

Document type

Dissertation

Publisher

Hypertension and Cardiovascular Disease

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • NEDD4L
  • SGK-1
  • CVD
  • ischemic stroke
  • genetics
  • CVD deaths
  • myopcardial infarction

Status

Published

Research group

  • Cardiovascular Research - Hypertension

Supervisor

  • Olle Melander
  • Fredrik Wowern

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-7619-003-6

Defence date

7 June 2014

Defence time

09:00

Defence place

Jan Waldenströms gata 47, Skånes Universitetssjukhus i Malmö

Opponent

  • Vicente Lahera (Professor)