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

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posted on 05.10.2021, 18:06 by Ruifang Li-Gao, David A. Hughes, Jan B. van Klinken, Renée de Mutsert, Frits R. Rosendaal, Dennis O. Mook-Kanamori, Nicholas J Timpson, Ko Willems van Dijk
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 set out to examine the genetics of variation in concentrations of postprandial metabolites (t=150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity study (N=5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (beta (SE): -0.23 (0.03), P-value: 2.15×10-19). In addition, ANKRD55 locus led by rs458741:C showed strong associations to extremely large VLDL particle (XXLVLDL) response (with XXLVLDLC: beta (SE): 0.17 (0.03) P-value: 5.76×10-10 and with XXLVLDLCE: beta (SE): 0.17 (0.03), P-value: 9.74×10-10), which also revealed strong associations to body composition and diabetes in the UK Biobank (p-values<5×10-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, ISI matsuda index and HbA1c in the NEO study further implied the role of chylomicron synthesis in diabetes (with FDR corrected q-value<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 ANKRD55 locus underlying diabetes.

Funding

The NEO study is supported by the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023).

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