Serotonin is elevated in risk-genotype carriers of TCF7L2 - rs7903146

Andreas Leiherer,Christoph H Saely,Heinz Drexel,Peter Fraunberger,Axel Muendlein

doi:10.1038/s41598-019-49347-y

Abstract

The transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146 is known to be tightly associated with an elevated risk for type 2 diabetes, whereas the molecular mechanisms remain elusive. We evaluated the metabolic profile of a total of 394 patients’ serum samples with respect to their rs7903146 genotype using targeted metabolomics in a discovery (n = 154) and a validation (n = 240) study. We have identified serotonin as the top metabolite being increased in carriers of the risk allele. Serotonin was significantly associated with the rs7903146 genotype after full adjustment including type 2 diabetes and further top ranked metabolites. Given the role of peripheral serotonin in metabolic homeostasis and type 2 diabetes, this finding provides a first hint that the well-known impact of the TCF7L2 polymorphism on type 2 diabetes risk may involve a serotonin-dependent pathway.

Highlights

Development of type 2 diabetes is linked with dysregulated metabolism
Allele combination were enrolled for metabolomics studies
As genome wide association studies (GWAS) with serotonin as phenotype did not identify a genomic region with genome-wide significance, we focused on the locus of the transcription factor 7-like 2 (TCF7L2) gene (position 112.910 kb and 113.278 kb (GRCh38.7); chromosome 10) and obtained a hint for an association between the TCF7L2 gene and serotonin concentration (Supplementary Fig. 6)

Summary

Introduction

Development of type 2 diabetes is linked with dysregulated metabolism. The role of metabolic homeostasis and cellular sensors has recently drawn attention to peripheral serotonin which is elevated in diabetic subjects[1,2]. A previous metabolomics profiling of 41 KORA study participants carried out in conjunction with a glucose tolerance test revealed alterations in phospholipid metabolism in individuals with the risk TCF7L2 genotype. A non-targeted metabolomics profiling of 30 TUEF study participants revealed no difference between homozygous carriers and non-carriers of the risk allele[16]. In view of this inconsistency, we analysed the metabolic alterations in a much larger patient population, comprising of a discovery and a validation cohort with a total of 394 patients

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Discussion

Conclusion