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

      research-article
      1 , 1 , 2 , 3 , 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 1 , 11 , 2 , 7 , 3 , 12 , 8 , 9 , 11 , 13 , 14 , 11 , 13 , 15 , 16 , 17 , 11 , 2 , 18 , 2 , 19 , 20 , 21 , 22 , 11 , 13 , 8 , 9 , 10 , 23 , 7 , 24 , 7 , 3 , 1 , 25 , 10 , 26 , 19 , 19 , 4 , 5 , 3 , 27 , 7 , 28 , 7 , 29 , 30 , 31 , 32 , 1 , , 1 , , BBMRI Metabolomics Consortium 7
      BMC Medicine
      BioMed Central
      Thyroid hormones, Coronary artery disease, Metabolomics, Mendelian randomization

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          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.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12916-021-02130-1.

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          Most cited references58

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          Complex heatmaps reveal patterns and correlations in multidimensional genomic data.

          Parallel heatmaps with carefully designed annotation graphics are powerful for efficient visualization of patterns and relationships among high dimensional genomic data. Here we present the ComplexHeatmap package that provides rich functionalities for customizing heatmaps, arranging multiple parallel heatmaps and including user-defined annotation graphics. We demonstrate the power of ComplexHeatmap to easily reveal patterns and correlations among multiple sources of information with four real-world datasets.
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            Conducting Meta-Analyses inRwith themetaforPackage

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              UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age

              Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.
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                Author and article information

                Contributors
                r.noordam@lumc.nl
                d.van_heemst@lumc.nl
                Journal
                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central (London )
                1741-7015
                3 November 2021
                3 November 2021
                2021
                : 19
                : 266
                Affiliations
                [1 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Internal Medicine, Section of Gerontology and Geriatrics, , Leiden University Medical Center, ; PO Box 9600, 2300 RC Leiden, The Netherlands
                [2 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Epidemiology, , Erasmus MC, ; Rotterdam, The Netherlands
                [3 ]GRID grid.16872.3a, ISNI 0000 0004 0435 165X, Amsterdam UMC, Vrije Universiteit, Department of Psychiatry, , Amsterdam Public Health research institute, ; Amsterdam, The Netherlands
                [4 ]GRID grid.5645.2, ISNI 000000040459992X, Academic Center for Thyroid Diseases, , Erasmus MC, ; Rotterdam, The Netherlands
                [5 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Internal Medicine, , Erasmus MC, ; Rotterdam, The Netherlands
                [6 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Computational Medicine, Berlin Institute of Health (BIH), , Charité-Universitätsmedizin Berlin, ; Berlin, Germany
                [7 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Biomedical Data Sciences, section of Molecular Epidemiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [8 ]GRID grid.410556.3, ISNI 0000 0001 0440 1440, NIHR Oxford Biomedical Research Centre, , Oxford University Hospitals Foundation Trust, ; Oxford, UK
                [9 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, , University of Oxford, ; Oxford, UK
                [10 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Clinical Epidemiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [11 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, , Imperial College London, ; London, UK
                [12 ]GRID grid.5603.0, Institute of Clinical Chemistry and Laboratory Medicine, , University Medicine Greifswald, ; Greifswald, Germany
                [13 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Dementia Research Institute at Imperial College London, ; London, UK
                [14 ]GRID grid.8756.c, ISNI 0000 0001 2193 314X, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, , University of Glasgow, ; Glasgow, UK
                [15 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, NIHR Biomedical Research Centre, , Imperial College London, ; London, UK
                [16 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, BHF Imperial College Centre for Research Excellence, , Imperial College London, ; London, UK
                [17 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Department of Mathematics, Faculty of Natural Sciences, , Imperial College London, ; London, UK
                [18 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Laboratory Medicine, Radboud Laboratory for Diagnostics (RLD), , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [19 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Internal Medicine, Division of Endocrinology, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [20 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Internal Medicine and Radboud Center for Infectious Diseases, , Radboud University Medical Center, ; Nijmegen, The Netherlands
                [21 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Cardiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [22 ]GRID grid.411737.7, Netherlands Heart Institute, ; Utrecht, The Netherlands
                [23 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Rheumatology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [24 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Orthopaedics, , Leiden University Medical Center, ; Leiden, The Netherlands
                [25 ]Institute for Evidence-Based Medicine in Old Age (IEMO), Leiden, The Netherlands
                [26 ]GRID grid.10419.3d, ISNI 0000000089452978, 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 ]GRID grid.419502.b, ISNI 0000 0004 0373 6590, Max Planck Institute for Biology of Ageing, ; Cologne, Germany
                [29 ]GRID grid.5603.0, Institute for Community Medicine, , University Medicine Greifswald, ; Greifswald, Germany
                [30 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Human Genetics, , Leiden University Medical Center, ; Leiden, The Netherlands
                [31 ]GRID grid.10419.3d, ISNI 0000000089452978, Department of Internal Medicine, Division of Endocrinology, , Leiden University Medical Center, ; Leiden, The Netherlands
                [32 ]GRID grid.10419.3d, ISNI 0000000089452978, Einthoven Laboratory for Experimental Vascular Medicine, , Leiden University Medical Center, ; Leiden, The Netherlands
                Author information
                http://orcid.org/0000-0001-7801-809X
                Article
                2130
                10.1186/s12916-021-02130-1
                8565073
                34727949
                94472392-8632-48a9-b8fa-30980e0361ce
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 12 May 2021
                : 16 September 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100010661, Horizon 2020 Framework Programme;
                Award ID: 666869
                Funded by: NWO
                Award ID: 184.021.007
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2021

                Medicine
                thyroid hormones,coronary artery disease,metabolomics,mendelian randomization
                Medicine
                thyroid hormones, coronary artery disease, metabolomics, mendelian randomization

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