Testing for a causal role of thyroid hormone measurements within the normal range on human metabolism and diseases: a systematic Mendelian randomization.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-09-01 Epub Date: 2024-08-26 DOI:10.1016/j.ebiom.2024.105306

Heba Alwan, Jian'an Luan, Alice Williamson, Julia Carrasco-Zanini, Isobel D Stewart, Nicholas J Wareham, Claudia Langenberg, Maik Pietzner

{"title":"Testing for a causal role of thyroid hormone measurements within the normal range on human metabolism and diseases: a systematic Mendelian randomization.","authors":"Heba Alwan, Jian'an Luan, Alice Williamson, Julia Carrasco-Zanini, Isobel D Stewart, Nicholas J Wareham, Claudia Langenberg, Maik Pietzner","doi":"10.1016/j.ebiom.2024.105306","DOIUrl":null,"url":null,"abstract":"Background: Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown.Methods: We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases.Findings: Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio = 0.92, p-value = 2.13 × 10-3), thyroid cancer (odds ratio = 0.57, p-value = 2.97 × 10-4), and specific biomarkers, such as sex hormone binding globulin (β = -0.046, p-value = 1.33 × 10-6) and total cholesterol (β = 0.027, p-value = 5.80 × 10-3).Interpretation: In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding.Funding: This research was funded by the Swiss National Science Foundation (P1BEP3_200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1, MC_PC_13046 and MC_UU_00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048 and MC_UU_00006/1).","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11400601/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EBioMedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ebiom.2024.105306","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown.

Methods: We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases.

Findings: Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio = 0.92, p-value = 2.13 × 10^-3), thyroid cancer (odds ratio = 0.57, p-value = 2.97 × 10^-4), and specific biomarkers, such as sex hormone binding globulin (β = -0.046, p-value = 1.33 × 10^-6) and total cholesterol (β = 0.027, p-value = 5.80 × 10^-3).

Interpretation: In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding.

Funding: This research was funded by the Swiss National Science Foundation (P1BEP3_200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1, MC_PC_13046 and MC_UU_00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048 and MC_UU_00006/1).

查看原文本刊更多论文

测试正常范围内的甲状腺激素测量值对人体新陈代谢和疾病的因果作用：系统性孟德尔随机试验。

背景：据观察，甲状腺功能参数在正常范围内的变化与不良健康结果有关。这些关联是否反映了因果效应，目前尚不清楚：我们在三个大型人群队列中系统检测了正常范围内促甲状腺激素（TSH）和游离甲状腺素（FT4）的遗传差异与 1100 多种疾病和 6000 多种分子特征（代谢物和蛋白质）之间的关联。这项研究结合了个体和汇总水平的遗传数据，并使用了多基因评分和孟德尔随机化（MR）方法。我们在涵盖数千种复杂表型和疾病的 OpenGWAS 数据库中进行了全表型 MR 研究：遗传预测的 TSH 或 FT4 水平在正常范围内主要与甲状腺相关结果有关，如甲状腺肿。少数甲状腺以外的结果与 TSH 水平偏高但正常的遗传相关，包括心房颤动（几率比 = 0.92，P 值 = 2.13 × 10-3）、甲状腺癌（几率比 = 0.57, p-value = 2.97 × 10-4），以及特定的生物标志物，如性激素结合球蛋白（β = -0.046, p-value = 1.33 × 10-6）和总胆固醇（β = 0.027, p-value = 5.80 × 10-3）：与以往描述甲状腺激素水平与疾病结果之间关系的研究相比，我们的遗传学方法几乎没有发现正常范围内甲状腺功能的遗传差异与非甲状腺表型之间存在关联的证据。以往研究中描述的关联可能是由反向因果关系和混杂因素造成的：本研究由瑞士国家科学基金会（P1BEP3_200041）资助。芬兰研究（DOI 10.22025/2017.10.101.00001）由医学研究委员会（MC_UU_12015/1、MC_PC_13046和MC_UU_00006/1）资助。EPIC-Norfolk研究（DOI 10.22025/2019.10.105.00004）得到了医学研究委员会（MR/N003284/1、MC-UU_12015/1、MC_PC_13048和MC_UU_00006/1）的资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.

文献相关原料

公司名称	产品信息	采购帮参考价格