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

Tarun Veer Singh Ahluwalia; Jesper Thorvald Troelsen; Marie Balslev-Harder; Jette Bork-Jensen; Betina Heinsbæk Thuesen; Charlotte Cerqueira; Allan Linneberg; Niels Grarup; Oluf Pedersen; Torben Hansen; Louise Torp Dalgaard

doi:10.1136/jmedgenet-2016-104084

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

Tarun Veer Singh Ahluwalia, Jesper Thorvald Troelsen, Marie Balslev-Harder, Jette Bork-Jensen, Betina Heinsbæk Thuesen, Charlotte Cerqueira, Allan Linneberg, Niels Grarup, Oluf Pedersen, Torben Hansen, Louise Torp Dalgaard

Institut for Klinisk Medicin

6 Citationer (Scopus)

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/EBPß (ccaat enhancer binding protein ß). 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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medical Genetics
Vol/bind	54
Udgave nummer	3
Sider (fra-til)	166-175
Antal sider	10
ISSN	0022-2593
DOI	https://doi.org/10.1136/jmedgenet-2016-104084
Status	Udgivet - 1 mar. 2017

Adgang til dokumentet

10.1136/jmedgenet-2016-104084

Citationsformater

Ahluwalia, T. V. S., Troelsen, J. T., Balslev-Harder, M., Bork-Jensen, J., Thuesen, B. H., Cerqueira, C., Linneberg, A., Grarup, N., Pedersen, O., Hansen, T., & Dalgaard, L. T. (2017). Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone. Journal of Medical Genetics, 54(3), 166-175. https://doi.org/10.1136/jmedgenet-2016-104084

Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone. / Ahluwalia, Tarun Veer Singh; Troelsen, Jesper Thorvald; Balslev-Harder, Marie et al.

I: Journal of Medical Genetics, Bind 54, Nr. 3, 01.03.2017, s. 166-175.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Ahluwalia, TVS, Troelsen, JT, Balslev-Harder, M, Bork-Jensen, J, Thuesen, BH, Cerqueira, C, Linneberg, A , Grarup, N , Pedersen, O , Hansen, T & Dalgaard, LT 2017, 'Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone', Journal of Medical Genetics, bind 54, nr. 3, s. 166-175. https://doi.org/10.1136/jmedgenet-2016-104084

@article{2641c1db7d474daca82893b0bdeee055,

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

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/EBP{\ss} (ccaat enhancer binding protein {\ss}). 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.",

author = "Ahluwalia, {Tarun Veer Singh} and Troelsen, {Jesper Thorvald} and Marie Balslev-Harder and Jette Bork-Jensen and Thuesen, {Betina Heinsb{\ae}k} and Charlotte Cerqueira and Allan Linneberg and Niels Grarup and Oluf Pedersen and Torben Hansen and Dalgaard, {Louise Torp}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

year = "2017",

month = mar,

day = "1",

doi = "10.1136/jmedgenet-2016-104084",

language = "English",

volume = "54",

pages = "166--175",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

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TY - JOUR

T1 - Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone

AU - Ahluwalia, Tarun Veer Singh

AU - Troelsen, Jesper Thorvald

AU - Balslev-Harder, Marie

AU - Bork-Jensen, Jette

AU - Thuesen, Betina Heinsbæk

AU - Cerqueira, Charlotte

AU - Linneberg, Allan

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Dalgaard, Louise Torp

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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/EBPß (ccaat enhancer binding protein ß). 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.

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/EBPß (ccaat enhancer binding protein ß). 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.

U2 - 10.1136/jmedgenet-2016-104084

DO - 10.1136/jmedgenet-2016-104084

M3 - Journal article

C2 - 27627987

SN - 0022-2593

VL - 54

SP - 166

EP - 175

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 3

ER -

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

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