AUTHOR=Jaghutriz Benjamin Assad , Heni Martin , Lutz Stefan Zoltán , Fritsche Louise , Machicao Fausto , Staiger Harald , Peter Andreas , Häring Hans-Ulrich , Fritsche Andreas , Wagner Róbert 

TITLE=Gene x Gene Interactions Highlight the Role of Incretin Resistance for Insulin Secretion

JOURNAL=Frontiers in Endocrinology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2019.00072

DOI=10.3389/fendo.2019.00072

ISSN=1664-2392

ABSTRACT=<p><bold>Introduction:</bold> Genetic polymorphisms in <italic>TCF7L2</italic> are the strongest common risk variants for type 2 diabetes mellitus (T2D). We and others have shown that genetic variation in <italic>TCF7L2</italic> and <italic>WFS1</italic> 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 <italic>TCF7L2</italic> variant rs7903146 on insulin secretion due to their incretin altering effect.</p><p><bold>Methods:</bold> In this retrospective analysis, we used data from the cross-sectional TUEF-cohort (<italic>n</italic> = 2929) and a hyperglycemic clamp study using additional GLP-1 infusion at the end of the clamp (<italic>n</italic> = 76). Insulin secretion was measured by evaluating OGTT-derived indexes of insulin secretion and insulin/C-peptide levels during clamp. We genotyped rs7903146 in <italic>TCF7L2</italic>, rs10010131 in <italic>WFS1</italic>, and six SNPs associated with GLP-1 and GIP levels.</p><p><bold>Results:</bold> One of the six incretin-associated SNPs, rs17681684 in <italic>GLP2R</italic>, exhibited significant SNP x SNP interactions with rs7903146 in <italic>TCF7L2</italic> on insulin secretion (<italic>p</italic> = 0.0024) after correction for multiple testing. Three further SNP‘s showed nominally significant interactions (<italic>p</italic> &lt; 0.05). In the hyperglycemic clamp study, rs7903146 in <italic>TCF7L2</italic> also interacted with rs17681684 on AUC C-peptide during the GLP-1 stimulation phase, thereby replicating the above finding.</p><p><bold>Conclusion:</bold> 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.</p>