Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study

Aleksander Kuś; Eirini Marouli; Fabiola Del Greco M.; Layal Chaker; Tomasz Bednarczuk; Robin P. Peeters; Alexander Teumer; Marco Medici; Panos Deloukas

doi:10.1089/thy.2020.0393

Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study

Aleksander Kuś^*
, Eirini Marouli
, Fabiola Del Greco M.
, Layal Chaker
, Tomasz Bednarczuk
, Robin P. Peeters
, Alexander Teumer
, Marco Medici
, Panos Deloukas

^*Corresponding author for this work

Medical University of Warsaw
Barts and The London School of Medicine and Dentistry
Queen Mary University of London
EURAC Research
King Abdulaziz University
University Medicine Greifswald
Partner Site Greifswald
Radboud University Medical Center

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 × 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (β = 0.026 SD, p = 1.9 × 10-3), pulse pressure (β =-0.477 mmHg, p = 7.5 × 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 × 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 × 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.

Original language	English
Pages (from-to)	721-731
Number of pages	11
Journal	Thyroid
Volume	31
Issue number	5
DOIs	https://doi.org/10.1089/thy.2020.0393
Publication status	Published - 3 May 2021

Bibliographical note

Funding Information:
This work was supported by the Exchange in Endocrinology Expertise (3E) program of the European Union of Medical Specialists (UEMS), Section and Board of Endocrinology (A.K.). This work was supported by funding from the European and American Thyroid Associations, the Erasmus University Rotterdam, and the Dutch Organization for Scientific Research (NWO) (M.M.). This work was supported by the British Heart Foundation (BHF) grant RG/14/5/ 30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR).

Publisher Copyright:
© 2021, Mary Ann Liebert, Inc., publishers.

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Cite this

@article{ecc21d28902441c7992351a8209ef85f,

title = "Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study",

abstract = "Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 {\texttimes} 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (β = 0.026 SD, p = 1.9 {\texttimes} 10-3), pulse pressure (β =-0.477 mmHg, p = 7.5 {\texttimes} 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 {\texttimes} 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 {\texttimes} 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.",

author = "Aleksander Ku{\'s} and Eirini Marouli and \{Del Greco M.\}, Fabiola and Layal Chaker and Tomasz Bednarczuk and Peeters, \{Robin P.\} and Alexander Teumer and Marco Medici and Panos Deloukas",

note = "Funding Information: This work was supported by the Exchange in Endocrinology Expertise (3E) program of the European Union of Medical Specialists (UEMS), Section and Board of Endocrinology (A.K.). This work was supported by funding from the European and American Thyroid Associations, the Erasmus University Rotterdam, and the Dutch Organization for Scientific Research (NWO) (M.M.). This work was supported by the British Heart Foundation (BHF) grant RG/14/5/ 30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). Publisher Copyright: {\textcopyright} 2021, Mary Ann Liebert, Inc., publishers.",

year = "2021",

month = may,

day = "3",

doi = "10.1089/thy.2020.0393",

language = "English",

volume = "31",

pages = "721--731",

journal = "Thyroid",

issn = "1050-7256",

publisher = "SAGE Publications Ltd",

number = "5",

}

TY - JOUR

T1 - Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk

T2 - A Mendelian Randomization Study

AU - Kuś, Aleksander

AU - Marouli, Eirini

AU - Del Greco M., Fabiola

AU - Chaker, Layal

AU - Bednarczuk, Tomasz

AU - Peeters, Robin P.

AU - Teumer, Alexander

AU - Medici, Marco

AU - Deloukas, Panos

N1 - Funding Information: This work was supported by the Exchange in Endocrinology Expertise (3E) program of the European Union of Medical Specialists (UEMS), Section and Board of Endocrinology (A.K.). This work was supported by funding from the European and American Thyroid Associations, the Erasmus University Rotterdam, and the Dutch Organization for Scientific Research (NWO) (M.M.). This work was supported by the British Heart Foundation (BHF) grant RG/14/5/ 30893 (P.D.) and forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). Publisher Copyright: © 2021, Mary Ann Liebert, Inc., publishers.

PY - 2021/5/3

Y1 - 2021/5/3

N2 - Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 × 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (β = 0.026 SD, p = 1.9 × 10-3), pulse pressure (β =-0.477 mmHg, p = 7.5 × 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 × 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 × 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.

AB - Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 × 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (β = 0.026 SD, p = 1.9 × 10-3), pulse pressure (β =-0.477 mmHg, p = 7.5 × 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 × 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 × 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.

UR - https://www.scopus.com/pages/publications/85105746042

U2 - 10.1089/thy.2020.0393

DO - 10.1089/thy.2020.0393

M3 - Article

C2 - 32746749

AN - SCOPUS:85105746042

SN - 1050-7256

VL - 31

SP - 721

EP - 731

JO - Thyroid

JF - Thyroid

IS - 5

ER -

Variation in Normal Range Thyroid Function Affects Serum Cholesterol Levels, Blood Pressure, and Type 2 Diabetes Risk: A Mendelian Randomization Study

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