RT Journal Article SR Electronic T1 Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 166 OP 175 DO 10.1136/jmedgenet-2016-104084 VO 54 IS 3 A1 Ahluwalia, Tarunveer Singh A1 Troelsen, Jesper Thorvald A1 Balslev-Harder, Marie A1 Bork-Jensen, Jette A1 Thuesen, Betina Heinsbæk A1 Cerqueira, Charlotte A1 Linneberg, Allan A1 Grarup, Niels A1 Pedersen, Oluf A1 Hansen, Torben A1 Dalgaard, Louise Torp YR 2017 UL http://jmg.bmj.com/content/54/3/166.abstract AB 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.