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.
Bibliografisk noteImportant note from the publisher:“This article has been accepted for publication in [Journal of Medical Genetics 2017] following peer review, and the Version of Record can be accessed online at 10.1136/jmedgenet-2016-104084.”
- Metabolic disorders
- Molecular genetics
- insulin resistance
- transcription factor