title: A missense variant in GLP1R gene is associated with the glycaemic response to treatment with gliptins.
abstract: Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment. GLP1R rs6923761 (Gly168Ser) and GIPR rs10423928 genotyping was performed using real-time PCR, with subsequent high-resolution melting analysis. The main study outcome was reduction in glycated haemoglobin (HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (β = -0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly-allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype-related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine.
authors.affiliation: Faculty of Medicine, Department of Internal Medicine 4, Šafárik University, Košice, Slovakia.|Department of Internal Medicine 4, Pasteur University Hospital, Košice, Slovakia.
authors.forename: M
authors.initials: M
authors.lastname: Javorský
authors.affiliation: Faculty of Medicine, Department of Internal Medicine 4, Šafárik University, Košice, Slovakia.|Department of Internal Medicine 4, Pasteur University Hospital, Košice, Slovakia.
authors.forename: I
authors.initials: I
authors.lastname: Gotthardová
authors.affiliation: Faculty of Medicine, Department of Internal Medicine 4, Šafárik University, Košice, Slovakia.|Faculty of Medicine, Department of Medicine Biology, Šafárik University, Košice, Slovakia.
authors.forename: L
authors.initials: L
authors.lastname: Klimčáková
authors.affiliation: Faculty of Medicine 2, Department of Medicine, Charles University, Praha, Czech Republic.|Faculty Hospital in Motol, Department of Medicine, Praha, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Kvapil
authors.affiliation: Faculty of Medicine, Department of Internal Medicine 4, Šafárik University, Košice, Slovakia.
authors.forename: J
authors.initials: J
authors.lastname: Židzik
authors.affiliation: Department of Internal Medicine 4, Pasteur University Hospital, Košice, Slovakia.
authors.forename: Z
authors.initials: Z
authors.lastname: Schroner
authors.affiliation: Faculty Hospital in Motol, Department of Medicine, Praha, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Doubravová
authors.affiliation: Department of Internal Medicine 4, Pasteur University Hospital, Košice, Slovakia.
authors.forename: I
authors.initials: I
authors.lastname: Gala
authors.affiliation: Faculty of Medicine, Department of Internal Medicine 4, Šafárik University, Košice, Slovakia.|Department of Internal Medicine 4, Pasteur University Hospital, Košice, Slovakia.
authors.forename: I
authors.initials: I
authors.lastname: Dravecká
authors.affiliation: Faculty of Medicine, Department of Internal Medicine 4, Šafárik University, Košice, Slovakia.|Department of Internal Medicine 4, Pasteur University Hospital, Košice, Slovakia.
authors.forename: I
authors.initials: I
authors.lastname: Tkáč
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D000071184:Pharmacogenomic Variants; D010865:Pilot Projects; D057285:Precision Medicine; D060888:Real-Time Polymerase Chain Reaction; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D011964:Receptors, Gastrointestinal Hormone; C000593833:GLP1R protein, human; C517652:hemoglobin A1c protein, human; C041086:gastric inhibitory polypeptide receptor
keywords: GLP1R polymorphism; dipeptidyl peptidase inhibitor; oral antidiabetic drug; pharmacogenetics