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Jaghutriz, B.A. ; Heni, M. ; Lutz, S.Z. ; Fritsche, L. ; Machicao, F. ; Staiger, H. ; Peter, A. ; Häring, H.-U. ; Fritsche, A. ; Wagner, R.

Gene X gene interactions highlight the role of incretin resistance for insulin secretion.

Front. Endocrin. 10:72 (2019)
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Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in TCF7L2 and WFS1 affect incretin-stimulated insulin secretion. A recent genome-wide association study discovered genetic variants associated with incretin levels. We hypothesized that these SNPs (single nucleotide polymorphisms) interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (n = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (n = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in TCF7L2, rs10010131 in WFS1, and six SNPs associated with GLP-1 and GIP levels. Results: One of the six incretin-associated SNPs, rs17681684 in GLP2R, exhibited significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion (p = 0.0024) after correction for multiple testing. Three further SNP‘s showed nominally significant interactions (p < 0.05). In the hyperglycemic clamp study, rs7903146 in TCF7L2 also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding. Conclusion: The findings exemplify the role of SNP x SNP interactions in the genetics of type 2 diabetes mellitus and corroborate the existence of clinically relevant differences in incretin sensitivity.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene X Gene Interactions ; Hyperglycemic Clamp ; Incretin Resistance ; Incretins ; Insulin Secretion ; Snp X Snp Interactions ; Tcf7l2 ; Wfs1; Tcf7l2; Variants; Sensitivity; Association; Hormones; Humans; Risk
Language
Publication Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 1664-2392
e-ISSN 1664-2392
Journal Frontiers in Endocrinology
Quellenangaben Volume: 10, Issue: , Pages: , Article Number: 72 Supplement: ,
Publisher Frontiers
Publishing Place Lausanne
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
Institute of Experimental Genetics (IEG)
POF-Topic(s) 90000 - German Center for Diabetes Research
30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
Genetics and Epidemiology
PSP Element(s) G-502400-001
G-500600-003
DOI 10.3389/fendo.2019.00072
WOS ID WOS:000459291600001
Scopus ID 85068955918
PubMed ID PMC6393347
Erfassungsdatum 2019-03-21
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