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

Line Engelbrechtsen,Anna Jonsson,Oluf Pedersen,Peter E Weeke,Kristine Færch,Jørgen K Kanters,Henrik Vestergaard,Anette Prior Gjesing,Daniel R Witte,Marit E Jørgensen,Yuvaraj Mahendran,Jens J Holst,Torben Jørgensen,Signe Torekov,Torben Hansen,Niels Grarup

doi:10.1186/s12863-018-0602-2

Abstract

BackgroundPatients 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.ResultsCarriers 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.ConclusionsTwo 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 registrationClinicalTrials.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).

Highlights

Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-gorelated gene have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia
We report that the minor A- allele of rs36210421 is associated with increased glucagon-like peptide-1 (GLP-1) and decreased glucose-dependent insulinotropic polypeptide (GIP) response to oral glucose stimulation, whereas the minor G-allele of rs1805123 is associated with decreased fasting plasma insulin and glucagon release
We demonstrate that the additive effect of both variants cause increased GIP secretion and suppressed glucagon secretion, suggesting that human ether-á-go-gorelated gene (hERG) potassium channels play an important role in regulation of incretin and pancreatic hormone release

Summary

Introduction

Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-gorelated 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. Loss-of-function mutations in the human ether-á-go-go related (hERG) gene result in a dysfunctional Kv11.1 voltagegated potassium channel causing delayed cardiac repolarization, and long QT syndrome (LQTS) with increased risk of cardiac arrhythmias and sudden death [1,2,3,4]. This has led to speculations that hERG channels may play a role in secretion of hormones from endocrine cells [9]

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