The complex genetic architecture of type 2 diabetes (T2D) includes gene-by-environment (G×E) and gene-by-gene (G×G) interactions. To identify genetic markers for G×E and G×G, we screened individual markers for patterns indicative of interactions (rQTL and vQTL). rQTL exist when the correlation between multiple glycemic traits varies by genotype and vQTL occur when the variance of a glycemic trait varies by genotype (potentially flagging G×G and G×E interactions). In the metformin and placebo arms of the DPP (n=1,762) we screened 280,965 exomic and intergenic SNPs with minor allele frequency >0.01, for rQTL and vQTL patterns in year one changes from baseline in glycemic traits (insulinogenic index [IGI], insulin sensitivity index [ISI], fasting glucose and fasting insulin). Covariates included baseline age and BMI, sex, and ancestry. Significant (P<1.8×10-7) vQTL and rQTL generated a priori hypotheses for G×G screens and individual G×E tests for a SNP × metformin treatment interaction. All P values were obtained via parametric bootstrapping. Several unique vQTL and rQTL were identified, leading to 6 nominally significant metformin treatment × SNP interactions (4 IGI, 1 insulin, 1 glucose) and 12 G×G interactions (all IGI) that exceeded experiment-wide significance (P<4.1×10-9). Of these loci, some are directly associated with incident diabetes, others act as rQTL to modify a glycemic trait’s risk relationship with diabetes (2 diabetes/glucose, 2 diabetes/insulin, 1 diabetes/IGI). rs3197999, an ISI/Insulin rQTL, is a possibly gene damaging missense mutation in MST1, a gene affecting β-cell apoptosis and insulin secretion that in DPP and other studies is associated with diabetes and other glycemic traits. This rQTL may also link MST1 with insulin sensitivity where ISI and insulin responses differentially vary by genotype. This study demonstrates evidence for context-dependent effects (G×G and G×E) and complexity of these T2D-related traits.


T.J. Maxwell: None. K.A. Jablonski: None. P.W. Franks: Research Support; Self; Eli Lilly and Company, Sanofi, Novo Nordisk A/S, Servier, Boehringer Ingelheim GmbH. Consultant; Self; Zoe Ltd. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. W.C. Knowler: None. K.J. Mather: Research Support; Self; Merck & Co., Inc., Sanofi-Aventis, Novo Nordisk A/S, Abbott. Advisory Panel; Self; Merck & Co., Inc. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen. D. Research Group: None.

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