Carriers of a VEGFA enhancer polymorphism selectively binding chop/ddit3 are predisposed to increased circulating levels of thyroid stimulating hormone

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
TidsskriftJournal of Medical Genetics
Vol/bind54
Udgave nummer3
Sider (fra-til)166-175
Antal sider12
ISSN0022-2593
DOI
StatusUdgivet - mar. 2017

Bibliografisk note

Important 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.”

Emneord

  • Metabolic disorders
  • Molecular genetics
  • insulin resistance
  • thyroíd
  • transcription factor

Citer dette

Ahluwalia, Tarunveer Singh ; Troelsen, Jesper ; Balslev-Harder, Marie ; Bork-Jensen, Jette ; Thuesen, Betina Heinsbæk ; Cerqueira, Charlotte ; Linneberg, Allan ; Grarup, Niels ; Pedersen, Oluf ; Hansen, Torben ; Dalgaard, Louise Torp. / Carriers of a VEGFA enhancer polymorphism selectively binding chop/ddit3 are predisposed to increased circulating levels of thyroid stimulating hormone. I: Journal of Medical Genetics. 2017 ; Bind 54, Nr. 3. s. 166-175.
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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/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.",
keywords = "Metabolic disorders, Molecular genetics, insulin resistance, thyro{\'i}d, transcription factor, Metabolic disorders, Molecular genetics, insulin resistance, thyro{\'i}d, transcription factor",
author = "Ahluwalia, {Tarunveer Singh} and Jesper Troelsen 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 = "Important 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.”",
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doi = "10.1136/jmedgenet-2016-104084",
language = "English",
volume = "54",
pages = "166--175",
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Carriers of a VEGFA enhancer polymorphism selectively binding chop/ddit3 are predisposed to increased circulating levels of thyroid stimulating hormone. / Ahluwalia, Tarunveer Singh; Troelsen, Jesper; Balslev-Harder, Marie; Bork-Jensen, Jette; Thuesen, Betina Heinsbæk; Cerqueira, Charlotte; Linneberg, Allan; Grarup, Niels; Pedersen, Oluf; Hansen, Torben; Dalgaard, Louise Torp.

I: Journal of Medical Genetics, Bind 54, Nr. 3, 03.2017, s. 166-175.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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, Tarunveer Singh

AU - Troelsen, Jesper

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 - Important 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.”

PY - 2017/3

Y1 - 2017/3

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/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.

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.

KW - Metabolic disorders

KW - Molecular genetics

KW - insulin resistance

KW - thyroíd

KW - transcription factor

KW - Metabolic disorders

KW - Molecular genetics

KW - insulin resistance

KW - thyroíd

KW - transcription factor

U2 - 10.1136/jmedgenet-2016-104084

DO - 10.1136/jmedgenet-2016-104084

M3 - Journal article

VL - 54

SP - 166

EP - 175

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 3

ER -