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Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses

BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfuncti...

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Autores principales: Engelbrechtsen, Line, Mahendran, Yuvaraj, Jonsson, Anna, Gjesing, Anette Prior, Weeke, Peter E., Jørgensen, Marit E., Færch, Kristine, Witte, Daniel R., Holst, Jens J., Jørgensen, Torben, Grarup, Niels, Pedersen, Oluf, Vestergaard, Henrik, Torekov, Signe, Kanters, Jørgen K., Hansen, Torben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857134/
https://www.ncbi.nlm.nih.gov/pubmed/29548277
http://dx.doi.org/10.1186/s12863-018-0602-2
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author Engelbrechtsen, Line
Mahendran, Yuvaraj
Jonsson, Anna
Gjesing, Anette Prior
Weeke, Peter E.
Jørgensen, Marit E.
Færch, Kristine
Witte, Daniel R.
Holst, Jens J.
Jørgensen, Torben
Grarup, Niels
Pedersen, Oluf
Vestergaard, Henrik
Torekov, Signe
Kanters, Jørgen K.
Hansen, Torben
author_facet Engelbrechtsen, Line
Mahendran, Yuvaraj
Jonsson, Anna
Gjesing, Anette Prior
Weeke, Peter E.
Jørgensen, Marit E.
Færch, Kristine
Witte, Daniel R.
Holst, Jens J.
Jørgensen, Torben
Grarup, Niels
Pedersen, Oluf
Vestergaard, Henrik
Torekov, Signe
Kanters, Jørgen K.
Hansen, Torben
author_sort Engelbrechtsen, Line
collection PubMed
description BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG (rs36210421 and rs1805123) on QT interval and plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon during an oral glucose tolerance test (OGTT). We used two population-based cohorts for evaluation of the effect of common variants in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1, GIP, insulin and glucagon during an OGTT. RESULTS: Carriers of either the minor A-allele of rs36210421 or the minor G-allele of rs1805123 had ~ 2 ms shorter QT interval per risk allele (p = 0.025 and p = 1.9 × 10(− 7)). Additionally, both variants were associated with alterations in pancreatic and gut hormone release among carriers. The minor A- allele of rs36210421 was associated with increased GLP-1 and decreased GIP response to oral glucose stimulation, whereas the minor G-allele of rs1805123 is associated with decreased fasting plasma insulin and glucagon release. A genetic risk score combining the two gene variants revealed reductions in glucose-stimulated GIP, as well as suppressed glucagon response to increased glucose levels during an OGTT. CONCLUSIONS: Two common missense polymorphisms of the Kv11.1 voltage-gated hERG potassium channel are associated with alterations in circulating levels of GIP and glucagon, suggesting that hERG potassium channels play a role in fasting and glucose-stimulated release of GIP and glucagon. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00289237). Trial retrospectively registered at February 9, 2006. Studies were approved by the Ethical Committee of the Central Denmark Region (journal no. 20080229) and by the Copenhagen County Ethical Committee (KA 98155). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12863-018-0602-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-58571342018-03-22 Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses Engelbrechtsen, Line Mahendran, Yuvaraj Jonsson, Anna Gjesing, Anette Prior Weeke, Peter E. Jørgensen, Marit E. Færch, Kristine Witte, Daniel R. Holst, Jens J. Jørgensen, Torben Grarup, Niels Pedersen, Oluf Vestergaard, Henrik Torekov, Signe Kanters, Jørgen K. Hansen, Torben BMC Genet Research Article BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG (rs36210421 and rs1805123) on QT interval and plasma levels of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon during an oral glucose tolerance test (OGTT). We used two population-based cohorts for evaluation of the effect of common variants in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1, GIP, insulin and glucagon during an OGTT. RESULTS: Carriers of either the minor A-allele of rs36210421 or the minor G-allele of rs1805123 had ~ 2 ms shorter QT interval per risk allele (p = 0.025 and p = 1.9 × 10(− 7)). Additionally, both variants were associated with alterations in pancreatic and gut hormone release among carriers. The minor A- allele of rs36210421 was associated with increased GLP-1 and decreased GIP response to oral glucose stimulation, whereas the minor G-allele of rs1805123 is associated with decreased fasting plasma insulin and glucagon release. A genetic risk score combining the two gene variants revealed reductions in glucose-stimulated GIP, as well as suppressed glucagon response to increased glucose levels during an OGTT. CONCLUSIONS: Two common missense polymorphisms of the Kv11.1 voltage-gated hERG potassium channel are associated with alterations in circulating levels of GIP and glucagon, suggesting that hERG potassium channels play a role in fasting and glucose-stimulated release of GIP and glucagon. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00289237). Trial retrospectively registered at February 9, 2006. Studies were approved by the Ethical Committee of the Central Denmark Region (journal no. 20080229) and by the Copenhagen County Ethical Committee (KA 98155). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12863-018-0602-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-16 /pmc/articles/PMC5857134/ /pubmed/29548277 http://dx.doi.org/10.1186/s12863-018-0602-2 Text en © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Engelbrechtsen, Line
Mahendran, Yuvaraj
Jonsson, Anna
Gjesing, Anette Prior
Weeke, Peter E.
Jørgensen, Marit E.
Færch, Kristine
Witte, Daniel R.
Holst, Jens J.
Jørgensen, Torben
Grarup, Niels
Pedersen, Oluf
Vestergaard, Henrik
Torekov, Signe
Kanters, Jørgen K.
Hansen, Torben
Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses
title Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses
title_full Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses
title_fullStr Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses
title_full_unstemmed Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses
title_short Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses
title_sort common variants in the herg (kcnh2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857134/
https://www.ncbi.nlm.nih.gov/pubmed/29548277
http://dx.doi.org/10.1186/s12863-018-0602-2
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