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<0.05). 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. Speaker's 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.