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

doi:10.1186/s12916-021-02130-1

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

BMC Med. 2021 Nov 3;19(1):266. doi: 10.1186/s12916-021-02130-1.

Authors

Nicolien A van Vliet¹, Maxime M Bos^{1

2}, Carisha S Thesing³, Layal Chaker^{2

4

5}, Maik Pietzner⁶, Evelyn Houtman⁷, Matt J Neville^{8

9}, Ruifang Li-Gao¹⁰, Stella Trompet¹, Rima Mustafa¹¹, Fariba Ahmadizar², Marian Beekman⁷, Mariska Bot³, Kathrin Budde¹², Constantinos Christodoulides^{8

9}, Abbas Dehghan^{11

13}, Christian Delles¹⁴, Paul Elliott^{11

13

15

16}, Marina Evangelou¹⁷, He Gao¹¹, Mohsen Ghanbari², Antonius E van Herwaarden¹⁸, M Arfan Ikram², Martin Jaeger^{19

20}, J Wouter Jukema^{21

22}, Ibrahim Karaman^{11

13}, Fredrik Karpe^{8

9}, Margreet Kloppenburg^{10

23}, Jennifer M T A Meessen^{7

24}, Ingrid Meulenbelt⁷, Yuri Milaneschi³, Simon P Mooijaart^{1

25}, Dennis O Mook-Kanamori^{10

26}, Mihai G Netea¹⁹, Romana T Netea-Maier¹⁹, Robin P Peeters^{4

5}, Brenda W J H Penninx³, Naveed Sattar²⁷, P Eline Slagboom^{7

28}, H Eka D Suchiman⁷, Henry Völzke²⁹, Ko Willems van Dijk^{30

31

32}, Raymond Noordam³³, Diana van Heemst³⁴; BBMRI Metabolomics Consortium

Affiliations

¹ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
² Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
³ Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, Amsterdam Public Health research institute, Amsterdam, The Netherlands.
⁴ Academic Center for Thyroid Diseases, Erasmus MC, Rotterdam, The Netherlands.
⁵ Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
⁶ Computational Medicine, Berlin Institute of Health (BIH), Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁷ Department of Biomedical Data Sciences, section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁸ NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK.
⁹ Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, UK.
¹⁰ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
¹¹ MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
¹² Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
¹³ Dementia Research Institute at Imperial College London, London, UK.
¹⁴ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
¹⁵ NIHR Biomedical Research Centre, Imperial College London, London, UK.
¹⁶ BHF Imperial College Centre for Research Excellence, Imperial College London, London, UK.
¹⁷ Department of Mathematics, Faculty of Natural Sciences, Imperial College London, London, UK.
¹⁸ Department of Laboratory Medicine, Radboud Laboratory for Diagnostics (RLD), Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁹ Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
²⁰ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
²¹ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
²² Netherlands Heart Institute, Utrecht, The Netherlands.
²³ Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
²⁴ Department of Orthopaedics, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Institute for Evidence-Based Medicine in Old Age (IEMO), Leiden, The Netherlands.
²⁶ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
²⁷ BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK.
²⁸ Max Planck Institute for Biology of Ageing, Cologne, Germany.
²⁹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
³⁰ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³¹ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
³² Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
³³ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. r.noordam@lumc.nl.
³⁴ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. d.van_heemst@lumc.nl.

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.

Keywords: Coronary artery disease; Mendelian randomization; Metabolomics; Thyroid hormones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Cardiovascular Diseases* / diagnosis
Cardiovascular Diseases* / epidemiology
Cardiovascular Diseases* / genetics
Female
Humans
Lipids
Male
Mendelian Randomization Analysis
Middle Aged
Thyrotropin*
Thyroxine
Young Adult

Substances

Lipids
Thyrotropin
Thyroxine

Abstract

Publication types

MeSH terms

Substances

Grants and funding