SNP x SNP Interactions Elucidate TCF7L2’s Physiology Conveying Incretin Action

Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes. We and others had showed that genetic variation in TCF7L2 affects incretin-stimulated insulin secretion. A recent genome-wide association study discovered variants associated with incretin levels. We hypothesized that these SNPs interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect. Methods: Insulin secretion was measured with OGTT-based indices that were calculated from insulin, C-peptide and glucose levels in the cross-sectional TUEF-cohort (n=2929). We also measured insulin secretion in a modified hyperglycemic clamp at 10 mmol/l, using additional GLP-1 infusion at the end of the clamp (n=76). Besides rs7903146 in TCF7L2 , we genotyped rs17681684 in GLP2R , rs1800437 in GIPR , rs17683011 in SLC5A1 , as well as 3 additional variants associated with GIP levels. Results: Four of the 6 incretin-associated SNPs exhibited at least nominally significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion measured by the corrected insulin response (CIR). In the hyperglycemic clamp study, rs7903146 in TCF7L2 interacted with rs1800437 ( GIPR ) on both AUC insulin and C-peptide, and rs17681684 ( GLP2R) on AUC C-peptide during the GLP-1 stimulation phase (p Conclusion: These findings corroborate the role of the TCF7L2 variant in mediating incretin action to increase diabetes risk. They highlight the importance of SNP x SNP interactions in the assessment of the genetic architecture of type 2 diabetes. Disclosure B. Jaghutriz: None. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker9s Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc.. S.Z. Lutz: None. H. Staiger: None. A. Peter: None. H. Haering: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. R. Wagner: None.