BMC Medicine (Nov 2021)
Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling
- 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
Affiliations
- Nicolien A. van Vliet
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Maxime M. Bos
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Carisha S. Thesing
- Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health research institute
- Layal Chaker
- Department of Epidemiology, Erasmus MC
- Maik Pietzner
- Computational Medicine, Berlin Institute of Health (BIH), Charité-Universitätsmedizin Berlin
- Evelyn Houtman
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center
- Matt J. Neville
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust
- Ruifang Li-Gao
- Department of Clinical Epidemiology, Leiden University Medical Center
- Stella Trompet
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Rima Mustafa
- MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Fariba Ahmadizar
- Department of Epidemiology, Erasmus MC
- Marian Beekman
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center
- Mariska Bot
- Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health research institute
- Kathrin Budde
- Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald
- Constantinos Christodoulides
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust
- Abbas Dehghan
- MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Christian Delles
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow
- Paul Elliott
- MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Marina Evangelou
- Department of Mathematics, Faculty of Natural Sciences, Imperial College London
- He Gao
- MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC
- Antonius E. van Herwaarden
- Department of Laboratory Medicine, Radboud Laboratory for Diagnostics (RLD), Radboud University Medical Center
- M. Arfan Ikram
- Department of Epidemiology, Erasmus MC
- Martin Jaeger
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- J. Wouter Jukema
- Department of Cardiology, Leiden University Medical Center
- Ibrahim Karaman
- MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
- Fredrik Karpe
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust
- Margreet Kloppenburg
- Department of Clinical Epidemiology, Leiden University Medical Center
- Jennifer M. T. A. Meessen
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center
- Ingrid Meulenbelt
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center
- Yuri Milaneschi
- Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health research institute
- Simon P. Mooijaart
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Dennis O. Mook-Kanamori
- Department of Clinical Epidemiology, Leiden University Medical Center
- Mihai G. Netea
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- Romana T. Netea-Maier
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center
- Robin P. Peeters
- Academic Center for Thyroid Diseases, Erasmus MC
- Brenda W. J. H. Penninx
- Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health research institute
- Naveed Sattar
- BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine
- P. Eline Slagboom
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center
- H. Eka D. Suchiman
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center
- Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald
- Ko Willems van Dijk
- Department of Human Genetics, Leiden University Medical Center
- Raymond Noordam
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- Diana van Heemst
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center
- BBMRI Metabolomics Consortium
- Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center
- DOI
- https://doi.org/10.1186/s12916-021-02130-1
- Journal volume & issue
-
Vol. 19,
no. 1
pp. 1 – 13
Abstract
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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