Associations of Cannabinoid and TCF7L2 Allelic Variations with Gastric Function, Satiation and GLP-1 Levels

Abstract

Purpose: Genetic variation in transcription factor 7-like 2 (TCF7L2), a regulator of GLP-1 synthesis, is strongly associated with type 2 diabetes mellitus. Genetic variation in the cannabinoid pathway is associated with obesity, GLP-1 secretion and glycemia. GLP-1 impairs gastric functions and increases satiation. Our hypothesis was that TCF7L2, fatty acid amide hydroxylase (FAAH), and cannabinoid receptor 1 (CNR1) gene variants are associated with satiation, gastric motor function and GLP-1 levels in humans. Methods: In 62 adults of European ancestry, TCF7L2 (rs7903146), FAAH (rs324420), and CNR1 (rs806378) polymorphisms were genotyped; the association with solid and liquid gastric emptying (GE), gastric volume (GV) and satiation (maximum tolerated volume and symptoms after nutrient drink test) were explored using a dominant genetic model, with gender and BMI as covariates. In 50 of the participants, we measured plasma GLP-1 during fasting and after ingestion of a nutrient drink. Results: The presence of the T allele compared to CC genotype in TCF7L2 was associated with reduced fasting GV (p=0.05) and accelerated GE of liquids (p=0.002). There was no significant association of TCF7L2 with gastric emptying of solids, gastric accommodation or satiation, fasting or postprandial GLP-1. CNR1 was associated with reduced fasting GV (p=0.031) and a modest, non-significant, association with GE of solids (p=0.17). FAAH was not associated with alterations in gastric motor functions, satiation or GLP-1. Conclusion: Our data suggest that TCF7L2 and CNR1, but not FAAH, are associated with variation in gastric function that may mediate predisposition to obesity.