Dataset Information

Variant rs17619600 in the gene encoding serotonin receptor 2B (HTR2B) increases the risk of gestational diabetes mellitus: a case-control study.

ABSTRACT:

Background

During pregnancy, the increase in maternal insulin resistance is compensated by hyperplasia and increased function of maternal pancreatic beta cells; the failure of this compensatory mechanism is associated with gestational diabetes mellitus (GDM). Serotonin participates in beta cell adaptation, acting downstream of the prolactin pathway; the blocking of serotonin receptor B (HTR2B) signaling in pregnant mice impaired beta cell expansion and caused glucose intolerance. Thus, given the importance of the serotoninergic system for the adaptation of beta cells to the increased insulin demand during pregnancy, we hypothesized that genetic variants (single nucleotide polymorphisms [SNPs]) in the gene encoding HTR2B could influence the risk of developing GDM.

Methods

This was a case-control study. Five SNPs (rs4973377, rs765458, rs10187149, rs10194776, and s17619600) in HTR2B were genotyped by real-time polymerase chain reaction in 453 women with GDM and in 443 pregnant women without GDM.

Results

Only the minor allele C of SNP rs17619600 conferred an increased risk for GDM in the codominant model (odds ratio [OR] 2.15; 95% confidence interval [CI] 1.53-3.09; P < 0.0001) and in the rare dominant model (OR 2.32; CI 1.61-3.37; P < 0.0001). No associations were found between the SNPs and insulin use, maternal weight gain, newborn weight, or the result of postpartum oral glucose tolerance test (OGTT). In the overall population, carriers of the XC genotype (rare dominant model) presented a higher area under the curve (AUC) of plasma glucose during the OGTT, performed for diagnostic purposes, compared with carriers of the TT genotype of rs17619600.

Conclusions

SNP rs17619600 in the HTR2B gene influences glucose homeostasis, probably affecting insulin release, and the presence of the minor allele C was associated with a higher risk of GDM.

SUBMITTER: Penno JRCZ

PROVIDER: S-EPMC10362639 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Publications

Variant rs17619600 in the gene encoding serotonin receptor 2B (HTR2B) increases the risk of gestational diabetes mellitus: a case-control study.

Penno Juliana Regina Chamlian Zucare JRCZ Santos-Bezerra Daniele Pereira DP Cavaleiro Ana Mercedes AM da Silva Sousa Ana Maria AM Zaccara Tatiana Assunção TA da Costa Rafaela Alkmin RA Francisco Rossana Pulcineli Vieira RPV Correa-Giannella Maria Lucia ML

European journal of medical research 20230721 1

<h4>Background</h4>During pregnancy, the increase in maternal insulin resistance is compensated by hyperplasia and increased function of maternal pancreatic beta cells; the failure of this compensatory mechanism is associated with gestational diabetes mellitus (GDM). Serotonin participates in beta cell adaptation, acting downstream of the prolactin pathway; the blocking of serotonin receptor B (HTR2B) signaling in pregnant mice impaired beta cell expansion and caused glucose intolerance. Thus, g ...[more]

PMID: 37480094

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Project description:Uveal melanoma (UM) remains the most common intraocular malignancy among diseases affecting the adult eye. The primary tumor disseminates to the liver in half of patients and leads to a 6 to 12-month survival rate, making UM a particularly aggressive type of cancer. Genomic analyses have led to the development of gene-expression profiles that can efficiently predict metastatic progression. Among these genes, that encoding the serotonin receptor 2B (HTR2B) represents the most discriminant from this molecular signature, its aberrant expression being the hallmark of UM metastatic progression. Recent evidence suggests that expression of HTR2B might be regulated through the Janus kinase/Signal Transducer and Activator of Transcription proteins (JAK/STAT) intracellular signalization pathway. However, little is actually known about the molecular mechanisms involved in the abnormally elevated expression of the HTR2B gene in metastatic UM and whether activated STAT proteins participates to this mechanism. In this study, we determined the pattern of STAT family members expressed in both primary tumors and UM cell-lines, and evaluated their contribution to HTR2B gene expression. Examination of the HTR2B promoter sequence revealed the presence of a STAT putative target site (5'-TTC (N)3 GAA3') located 280 bp upstream of the mRNA start site that is completely identical to the high affinity binding site recognized by these TFs. Gene profiling on microarrays provided evidence that metastatic UM cell lines with high levels of HTR2B also express high levels of STAT proteins whereas low levels of these TFs are observed in non-metastatic UM cells with low levels of HTR2B, suggesting that STAT proteins contribute to HTR2B gene expression in UM cells. All UM cell lines tested were found to express their own pattern of STAT proteins in Western blot analyses. Furthermore, T142 and T143 UM cells responded to interleukins IL-4 and IL-6 by increasing the phosphorylation status of STAT1. Most of all, expression of HTR2B also considerably increased in response to both IL-4 and IL-6 therefore providing evidence that HTR2B gene expression is modulated by STAT proteins in UM cells. The binding of STAT proteins to the -280 HTR2B/STAT site was also demonstrated by electrophoretic mobility shift assay (EMSA) analyses and site-directed mutation of that STAT site also abolished both IL-4 and IL-6 responsiveness in in vitro transfection analyses. The results of this study therefore demonstrate that members from the STAT family of TFs positively contribute to the expression of HTR2B in uveal melanoma.

Dataset Information

Variant rs17619600 in the gene encoding serotonin receptor 2B (HTR2B) increases the risk of gestational diabetes mellitus: a case-control study.

Background

Methods

Results

Conclusions

Publications

Variant rs17619600 in the gene encoding serotonin receptor 2B (HTR2B) increases the risk of gestational diabetes mellitus: a case-control study.

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