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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
- Source :
- Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', B M C Genetics, vol. 19, no. 1, 15, pp. 1-9 . https://doi.org/10.1186/s12863-018-0602-2, Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', BMC Genetics, vol. 19, 15 . https://doi.org/10.1186/s12863-018-0602-2, BMC Genetics, Vol 19, Iss 1, Pp 1-9 (2018), Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', B M C Genetics, vol. 19, no. 1, 15, pp. 15 . https://doi.org/10.1186/s12863-018-0602-2, Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', BMC Genetics, vol. 19, no. 1, pp. 15 . https://doi.org/10.1186/s12863-018-0602-2, BMC Genetics
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
ERG1 Potassium Channel
medicine.medical_treatment
Denmark
030204 cardiovascular system & hematology
Cohort Studies
0302 clinical medicine
HERG ion channel
Glucagon-Like Peptide 1
Risk Factors
Glucose homeostasis
Insulin
Glucose/metabolism
Genetics (clinical)
Randomized Controlled Trials as Topic
Genetics
education.field_of_study
biology
Glucose-dependent insulinotropic polypeptide (GIP)
Fasting
Long QT Syndrome/genetics
Potassium channel
Genetic risk score
3. Good health
Long QT Syndrome
Gain of Function Mutation
Female
Glucagon/blood
hormones, hormone substitutes, and hormone antagonists
Research Article
QT interval
medicine.medical_specialty
endocrine system
ERG1 Potassium Channel/genetics
lcsh:QH426-470
KCHN2
hERG
Population
Incretin
Gastric Inhibitory Polypeptide
Hypoglycemia
Incretins
Glucagon
Incretins/blood
03 medical and health sciences
Internal medicine
Glucagon-Like Peptide 1/blood
medicine
Humans
Glucose Tolerance Test/methods
education
Retrospective Studies
Aged
Glucose Tolerance Test
medicine.disease
lcsh:Genetics
Glucose
030104 developmental biology
Endocrinology
hERG ion channel
biology.protein
Gastric Inhibitory Polypeptide/blood
Glucagon-like peptide-1 (GLP-1)
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', B M C Genetics, vol. 19, no. 1, 15, pp. 1-9 . https://doi.org/10.1186/s12863-018-0602-2, Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', BMC Genetics, vol. 19, 15 . https://doi.org/10.1186/s12863-018-0602-2, BMC Genetics, Vol 19, Iss 1, Pp 1-9 (2018), Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', B M C Genetics, vol. 19, no. 1, 15, pp. 15 . https://doi.org/10.1186/s12863-018-0602-2, Engelbrechtsen, L, Mahendran, Y, Jonsson, A, Gjesing, A P, Weeke, P E, Jørgensen, M E, Færch, K, Witte, D R, Holst, J J, Jørgensen, T, Grarup, N, Pedersen, O, Vestergaard, H, Torekov, S, Kanters, J K & Hansen, T 2018, ' Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses ', BMC Genetics, vol. 19, no. 1, pp. 15 . https://doi.org/10.1186/s12863-018-0602-2, BMC Genetics
- Accession number :
- edsair.doi.dedup.....665a5c8aa6803c6af810b746f20a8dcd