Aleksander Kuś1,2,3, Eirini Marouli4,5, Fabiola Del Greco M6, Layal Chaker1,2, Tomasz Bednarczuk3, Robin P Peeters1,2, Alexander Teumer7,8, Marco Medici1,2,9, Panos Deloukas4,5,10. 1. Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands. 2. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. 3. Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland. 4. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. 5. Centre for Genomic Health, Life Sciences, Queen Mary University of London, London, United Kingdom. 6. Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lubeck, Bolzano, Italy. 7. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. 8. DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany. 9. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 10. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract
Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 × 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (β = 0.026 SD, p = 1.9 × 10-3), pulse pressure (β = -0.477 mmHg, p = 7.5 × 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 × 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 × 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.
Background: Observational studies have demonstrated that variation in normal range thyroid function is associated with major cardiovascular risk factors, including dyslipidemia, hypertension, type 2 diabetes (T2D), and obesity. As observational studies are prone to residual confounding, reverse causality, and selection bias, we used a Mendelian randomization (MR) approach to investigate whether these associations are causal or not. Methods: Two-sample MR analysis using data from the largest available genome-wide association studies on normal range thyrotropin (TSH) and free thyroxine (fT4) levels, serum lipid levels, blood pressure measurements, T2D, and obesity traits (body mass index [BMI] and waist/hip ratio). Results: A one standard deviation (SD) increase in genetically predicted TSH levels was associated with a 0.037 SD increase in total cholesterol levels (p = 3.0 × 10-4). After excluding pleiotropic instruments, we also observed significant associations between TSH levels and low-density lipoprotein levels (β = 0.026 SD, p = 1.9 × 10-3), pulse pressure (β = -0.477 mmHg, p = 7.5 × 10-10), and T2D risk (odds ratio = 0.95, p = 2.5 × 10-3). While we found no evidence of causal associations between TSH or fT4 levels and obesity traits, we found that a one SD increase in genetically predicted BMI was associated with a 0.075 SD decrease in fT4 levels (p = 3.6 × 10-4). Conclusions: Variation in normal range thyroid function affects serum cholesterol levels, blood pressure, and T2D risk.
Entities:
Keywords:
Mendelian randomization study; blood pressure; cardiovascular risk factors; normal range thyroid function; serum cholesterol levels; type 2 diabetes
Authors: Christina Ellervik; Samia Mora; Aleksander Kuś; Bjørn Åsvold; Eirini Marouli; Panos Deloukas; Rosalie B T M Sterenborg; Alexander Teumer; Stephen Burgess; Maria Sabater-Lleal; Jennifer Huffman; Andrew D Johnson; David-Alexandre Trégouet; Nicolas L Smith; Marco Medici; Paul S DeVries; Daniel I Chasman; Alisa D Kjaergaard Journal: Thyroid Date: 2021-08-05 Impact factor: 6.506
Authors: Aleksander Kuś; Alisa D Kjaergaard; Eirini Marouli; Fabiola Del Greco M; Rosalie B T M Sterenborg; Layal Chaker; Robin P Peeters; Tomasz Bednarczuk; Bjørn O Åsvold; Stephen Burgess; Panos Deloukas; Alexander Teumer; Christina Ellervik; Marco Medici Journal: Thyroid Date: 2021-05-26 Impact factor: 6.506
Authors: Oscar H Roa Dueñas; Anna C Van der Burgh; Till Ittermann; Symen Ligthart; M Arfan Ikram; Robin Peeters; Layal Chaker Journal: J Clin Endocrinol Metab Date: 2022-05-17 Impact factor: 6.134
Authors: Josephine Mensah-Kane; Amand F Schmidt; Aroon D Hingorani; Chris Finan; Yutang Chen; Stefan van Duijvenboden; Michele Orini; Pier D Lambiase; Andrew Tinker; Eirini Marouli; Patricia B Munroe; Julia Ramírez Journal: Front Genet Date: 2021-02-18 Impact factor: 4.772