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http://hdl.handle.net/10397/93658
Title: | Genetically determined TSH level within reference range is inversely associated with Alzheimer disease | Authors: | Li, GHY Cheung, CL Cheung, EYN Chan, WC Tan, KCB |
Issue Date: | Dec-2021 | Source: | Journal of clinical endocrinology and metabolism, Dec. 2021, v. 106, no. 12, p. e5064-e5074 | Abstract: | Context: Contradictory findings were reported in observational studies on the association of thyroid function (thyrotropin [TSH] and free thyroxine [FT4] levels) with Alzheimer disease (AD). Objective: This work aims to determine whether genetically determined TSH/FT4 levels within reference range are causally associated with AD. Methods: A bidirectional, 2-sample mendelian randomization (MR) study was conducted. With summary statistics from the largest genome-wide association studies (GWAS)/GWAS meta-analysis of TSH level(n≥ 54 288), FT4 level(n= 49 269), and AD (71 880 cases; 383 378 controls), we used an MR approach to evaluate the bidirectional causal relationship between TSH/FT4 levels and AD. The inverse-variance weighted method was adopted as the main analysis. Results: One SD increase in genetically determined TSH level within reference range was causally associated with a reduced risk of AD (odds ratio: 0.988; 95% CI, 0.977-0.998). A similar inverse association was observed in sex-specific analysis. The causal association was attenuated after adjustment for atrial fibrillation and blood pressure, suggesting they may mediate the causal pathway. A positive causal effect of AD on TSH level was detected only in male participants. This male-specific feedback loop may explain why the largest cohort study to date (Rotterdam Study) demonstrated a null observational association in men. Null association was observed between FT4 level and AD in both directions. Conclusion: Genetic predisposition to increased TSH level, even within reference range, may lower the risk of AD, with atrial fibrillation, systolic, and diastolic blood pressure as possible mediators. Given the higher magnitude of risk reduction observed in the Rotterdam Study, whether the causal estimates derived from this MR study are underestimated warrants further investigation. |
Keywords: | Alzheimer disease Free thyroxine Mendelian randomization Thyrotropin |
Publisher: | Oxford University Press | Journal: | Journal of clinical endocrinology and metabolism | ISSN: | 0021-972X | EISSN: | 1945-7197 | DOI: | 10.1210/clinem/dgab527 | Rights: | © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com The following publication Gloria Hoi-Yee Li, Ching-Lung Cheung, Elaine Yun-Ning Cheung, Wai-Chi Chan, Kathryn Choon-Beng Tan, Genetically Determined TSH Level Within Reference Range Is Inversely Associated With Alzheimer Disease, The Journal of Clinical Endocrinology & Metabolism, Volume 106, Issue 12, December 2021, Pages e5064–e5074 is available at https://doi.org/10.1210/clinem/dgab527. |
Appears in Collections: | Journal/Magazine Article |
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