Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism.

Abstract

Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites (<i>t</i> = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (<i>n</i> = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (β [SE] -0.23 [0.03], <i>P</i> = 2.15 × 10^-19). In addition, the <i>ANKRD55</i> locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: β [SE] 0.17 [0.03], <i>P</i> = 5.76 × 10^-10; XXLVLDL cholesterol ester: β [SE] 0.17 [0.03], <i>P</i> = 9.74 × 10^-10), which also revealed strong associations with body composition and diabetes in the UK Biobank (<i>P</i> < 5 × 10^-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, Matsuda insulin sensitivity index, and HbA_1c in the NEO study implied the role of chylomicron synthesis in diabetes (with false discovery rate-corrected <i>q</i> <0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of the <i>ANKRD55</i> locus underlying diabetes.