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

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.

Figure 1

Volcano plot. The volcano plot depicts the combination of metabolite ratios of wildtype and risk allele carriers (ratio) and t-test p-values (p) in the discovery study (A) and the validation study (B). The x-axis represents log2 (ratio), the Y-axis is −log10 (p), based on raw p-values. The black horizontal line represents threshold for p-value (0.05).

Figure 2

SAM plot. The plot depicts the observed relative differences versus the expected relative differences estimated by data permutation. The solid diagonal line indicates where these two measures are the same. The dotted lines are drawn at a distance of delta from the solid line. With a given delta of 1.0, four metabolites were identified to be significantly increased in the risk genotype (highlighted in green) according to an FDR of 3.59 E-2. Metabolites are listed in Supplementary Table 1.

Figure 3

Association between rs7903146 genotype and serotonin. The forest plot depicts the adjusted odds ratios and 95% CI derived from binary logistic regression analysis for the association between TCF7L2 rs7903146 genotype and serum serotonin concentration as a continuous variable with stepwise adjustment. Adjustment model 1, a univariate model, represents the association between the genotype and serotonin. Model 2 represents the association between the genotype and serotonin with the type 2 diabetes status as covariate. Model 3 accounts for the parameters included in model 2 and, in addition, the covariates age, gender, and body mass index. Model 4 accounts for the parameters included in model 3 and, in addition, the hypertension status, the sig. CAD status, and the current smoking status. Model 5 accounts for the parameters included in model 4 and, in addition, arginine and the phosphatidylcholine PC aa C38:6. DS denotes discovery study, VS validation study.

Figure 4

Main metabolic pathways in serotonin biosynthesis. AADC denotes aromatic L-amino-acid decarboxylase, AANAT aralkylamine N-acetyltransferase, ALDH aldehyde dehydrogenase, ASMT N-acetylserotonin O-methyltransferase, IDO indoleamine-pyrrole 2,3 dioxygenase, KFA Kynurenine formamidase, MAO Monoaminooxidase, TDO tryptophan 2,3 dioxygenase, TPH represents tryptophane hydroxylase.