Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital

Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Cardiac Troponin I and Incident Stroke in European Cohorts: Insights From the BiomarCaRE Project

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Evaluation of Serum Insulin-like Factor 3 Quantification by LC-MS/MS as a Biomarker of Leydig Cell Function

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Does Estimated Pulse Wave Velocity Add Prognostic Information? MORGAM Prospective Cohort Project

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Repositioning of the global epicentre of non-optimal cholesterol

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

BACKGROUND: Levels of serum thyroid-stimulating hormone (TSH) indicate thyroid function, because thyroid hormone negatively controls TSH release. Genetic variants in the vascular endothelial growth factor A (VEGFA) gene are associated with TSH levels. The aim of this study was to characterise the association of VEGFA variants with TSH in a Danish cohort and to identify and characterise functional variants.

METHODS: We performed an association study of the VEGFA locus for circulating TSH levels in 8445 Danish individuals. Lead variants were tested for allele-specific effects in vitro using luciferase reporter and gel-shift assays.

RESULTS: Four SNPs in VEGFA were associated with circulating TSH (rs9472138, rs881858, rs943080 and rs4711751). For rs881858, the presence of each G-allele was associated with a corresponding decrease in TSH levels of 2.3% (p=8.4×10(-9)) and an increase in circulating free T4 levels (p=0.0014). The SNP rs881858 is located in a binding site for CHOP (C/EBP homology protein) and c/EBPβ (ccaat enhancer binding protein β). Reporter-gene analysis showed increased basal enhancer activity of the rs881858 A-allele versus the G-allele (34.5±9.9% (average±SEM), p=0.0012), while co-expression of CHOP effectively suppressed the rs881858 A-allele activity. The A-allele showed stronger binding to CHOP in gel-shift assays.

CONCLUSIONS: VEGF is an important angiogenic signal required for tissue expansion. We show that VEGFA variation giving allele-specific response to transcription factors with overlapping binding sites associate closely with circulating TSH levels. Because CHOP is induced by several types of intracellular stress, this indicates that cellular stress could be involved in the normal or pathophysiological response of the thyroid to TSH.

TRIAL REGISTRATION NUMBER: NCT00289237, NCT00316667; Results.

Original languageEnglish
JournalJournal of Medical Genetics
Issue number3
Pages (from-to)166-175
Publication statusPublished - Mar 2017

ID: 49848131