Abstract
Original language | English |
---|---|
Article number | 266 |
Journal | BMC medicine |
Volume | 19 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2021 |
Keywords
- Coronary artery disease
- Mendelian randomization
- Metabolomics
- Thyroid hormones
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In: BMC medicine, Vol. 19, No. 1, 266, 01.12.2021.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk
T2 - evidence from multi-cohort Mendelian randomization and metabolomic profiling
AU - van Vliet, Nicolien A.
AU - Bos, Maxime M.
AU - Thesing, Carisha S.
AU - Chaker, Layal
AU - Pietzner, Maik
AU - BBMRI Metabolomics Consortium
AU - Houtman, Evelyn
AU - Neville, Matt J.
AU - Li-Gao, Ruifang
AU - Trompet, Stella
AU - Mustafa, Rima
AU - Ahmadizar, Fariba
AU - Beekman, Marian
AU - Bot, Mariska
AU - Budde, Kathrin
AU - Christodoulides, Constantinos
AU - Dehghan, Abbas
AU - Delles, Christian
AU - Elliott, Paul
AU - Evangelou, Marina
AU - Gao, He
AU - Ghanbari, Mohsen
AU - van Herwaarden, Antonius E.
AU - Ikram, M. Arfan
AU - Jaeger, Martin
AU - Jukema, J. Wouter
AU - Karaman, Ibrahim
AU - Karpe, Fredrik
AU - Kloppenburg, Margreet
AU - Meessen, Jennifer M. T. A.
AU - Meulenbelt, Ingrid
AU - Milaneschi, Yuri
AU - Mooijaart, Simon P.
AU - Mook-Kanamori, Dennis O.
AU - Netea, Mihai G.
AU - Netea-Maier, Romana T.
AU - Peeters, Robin P.
AU - Penninx, Brenda W. J. H.
AU - Sattar, Naveed
AU - Slagboom, P. Eline
AU - Suchiman, H. Eka D.
AU - Völzke, Henry
AU - Willems van Dijk, Ko
AU - Noordam, Raymond
AU - van Heemst, Diana
N1 - Funding Information: This work in SHIP was funded by grants from the German Federal Ministry of Education and Research (BMBF, grants 01ZZ0403, 01ZZ0103, 01GI0883, AtheroSysMed 03IS2061B), the Ministry for Education, Research and Cultural Affairs, as well as the Ministry of Social Affairs of the Federal State of Mecklenburg-West Pomerania. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania (03IS2061A). Funding Information: The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Funding Information: The Airwave Health Monitoring Study was funded by the UK Home Office (780- TETRA, 2003-2018) and is currently funded by the MRC and ESRC (MR/R023484/1) with additional support from the NIHR Imperial College Biomedical Research Centre in collaboration with Imperial College NHS Healthcare Trust. PE acknowledges support from the MRC and PHE (MR/L01341X/1, 2014-2019) and currently from the MRC for the MRC Centre for Environment and Health (MR/S019669/1). PE is supported by the UK Dementia Research Institute which receives funding from UK DRI Ltd funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. PE is associate director of the Health Data Research UK London funded by a consortium led by the UK Medical Research Council. RM was supported by the President’s PhD Scholarships from Imperial College London. Funding Information: The OBB and Oxford BioResource are funded by the NIHR Oxford Biomedical Research Centre (BRC). CC is supported by an Intermediate Clinical Research Fellowship to (FS/16/45/32359) from the British Heart Foundation and FK from a BHF programme grant (RG/17/1/32663). Funding Information: The infrastructure for the NESDA study ( www.nesda.nl ) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). Funding Information: The GARP study is supported by Leiden University Medical Centre, Pfizer Groton, Connecticut, USA, and the Dutch Arthritis Society. Furthermore, the research leading to these results has received funding from the Biobanking and BioMolecular resources Research Infrastructure the Netherlands (BBMRI-NL) (complementation project CP2013-84), the Dutch Scientific Research council NWO/ZonMW VICI scheme (nr. 91816631/528) and the Dutch Arthritis Society. Funding Information: The 500FG was supported by an ERCConsolidator Grant (310372) and an IN-CONTROL CVON grant from the Dutch Heart Foundation (CVON2012-03 and CVON2018-27). MGN was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research (94-212). Funding Information: The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. JWJ is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). Funding Information: This work was supported by the European Commission project THYRAGE (Horizon 2020 research and innovation program, 666869) and BBMRI-NL, a research infrastructure financed by the Dutch Research Council (NWO, 184.021.007 and 184.033.111). Funding Information: The Leiden Longevity Study has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2011) under grant agreement number 259679, the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology and the Netherlands Consortium for Healthy Ageing (grant 050-060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), and BBMRI-NL, a Research Infrastructure financed by the Dutch Research Council (NWO 184.021.007 and 184.033.111). Publisher Copyright: © 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
KW - Coronary artery disease
KW - Mendelian randomization
KW - Metabolomics
KW - Thyroid hormones
UR - http://www.scopus.com/inward/record.url?scp=85118839624&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12916-021-02130-1
DO - https://doi.org/10.1186/s12916-021-02130-1
M3 - Article
C2 - 34727949
SN - 1741-7015
VL - 19
JO - BMC medicine
JF - BMC medicine
IS - 1
M1 - 266
ER -