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

Front. Endocrin. 10:72 (2019)
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Open Access Gold
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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 ; Snp X Snp Interactions ; Tcf7l2 ; Wfs1 ; Incretin Resistance ; Incretins ; Insulin Secretion ; Hyperglycemic Clamp; Tcf7l2; Variants; Sensitivity; Association; Hormones; Humans; Risk
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