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Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone
  1. Tarunveer Singh Ahluwalia1,2,
  2. Jesper Thorvald Troelsen3,
  3. Marie Balslev-Harder1,
  4. Jette Bork-Jensen1,
  5. Betina Heinsbæk Thuesen4,
  6. Charlotte Cerqueira4,
  7. Allan Linneberg4,5,6,
  8. Niels Grarup1,
  9. Oluf Pedersen1,
  10. Torben Hansen1,7,
  11. Louise Torp Dalgaard3
  1. 1The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  2. 2Steno Diabetes Center, Gentofte, Denmark
  3. 3Department of Science and Environment, Roskilde University, Roskilde, Denmark
  4. 4Research Centre for Prevention and Health, The Capital Region, Glostrup, Denmark
  5. 5Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark
  6. 6Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  7. 7Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  1. Correspondence to Dr Louise Torp Dalgaard, Department of Science and Environment, Roskilde University, Universitetsvej 1, Roskilde DK-4000, Denmark; ltd{at}ruc.dk

Abstract

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.

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