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Open Access 01-12-2021 | Hyperthyroidism | Research article

Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

Authors: Nicolien A. van Vliet, Maxime M. Bos, Carisha S. Thesing, Layal Chaker, Maik Pietzner, Evelyn Houtman, Matt J. Neville, Ruifang Li-Gao, Stella Trompet, Rima Mustafa, Fariba Ahmadizar, Marian Beekman, Mariska Bot, Kathrin Budde, Constantinos Christodoulides, Abbas Dehghan, Christian Delles, Paul Elliott, Marina Evangelou, He Gao, Mohsen Ghanbari, Antonius E. van Herwaarden, M. Arfan Ikram, Martin Jaeger, J. Wouter Jukema, Ibrahim Karaman, Fredrik Karpe, Margreet Kloppenburg, Jennifer M. T. A. Meessen, Ingrid Meulenbelt, Yuri Milaneschi, Simon P. Mooijaart, Dennis O. Mook-Kanamori, Mihai G. Netea, Romana T. Netea-Maier, Robin P. Peeters, Brenda W. J. H. Penninx, Naveed Sattar, P. Eline Slagboom, H. Eka D. Suchiman, Henry Völzke, Ko Willems van Dijk, Raymond Noordam, Diana van Heemst, BBMRI Metabolomics Consortium

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status.

Methods

Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction.

Results

Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04; p value 0.59).

Conclusions

Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

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Title: Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling
Authors: Nicolien A. van Vliet
Maxime M. Bos
Carisha S. Thesing
Layal Chaker
Maik Pietzner
Evelyn Houtman
Matt J. Neville
Ruifang Li-Gao
Stella Trompet
Rima Mustafa
Fariba Ahmadizar
Marian Beekman
Mariska Bot
Kathrin Budde
Constantinos Christodoulides
Abbas Dehghan
Christian Delles
Paul Elliott
Marina Evangelou
He Gao
Mohsen Ghanbari
Antonius E. van Herwaarden
M. Arfan Ikram
Martin Jaeger
J. Wouter Jukema
Ibrahim Karaman
Fredrik Karpe
Margreet Kloppenburg
Jennifer M. T. A. Meessen
Ingrid Meulenbelt
Yuri Milaneschi
Simon P. Mooijaart
Dennis O. Mook-Kanamori
Mihai G. Netea
Romana T. Netea-Maier
Robin P. Peeters
Brenda W. J. H. Penninx
Naveed Sattar
P. Eline Slagboom
H. Eka D. Suchiman
Henry Völzke
Ko Willems van Dijk
Raymond Noordam
Diana van Heemst
BBMRI Metabolomics Consortium
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Hyperthyroidism
Arterial Diseases
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02130-1

At a glance: The STEP trials

Springer Medicine

Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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