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 - 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 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
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 - https://www.scopus.com/pages/publications/85118839624
U2 - 10.1186/s12916-021-02130-1
DO - 10.1186/s12916-021-02130-1
M3 - Article
C2 - 34727949
AN - SCOPUS:85118839624
SN - 1741-7015
VL - 19
JO - BMC Medicine
JF - BMC Medicine
IS - 1
M1 - 266
ER -