Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; Institute for Medical Dataology, Shandong University, Jinan, Shandong, 250003, China.
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Department of Endocrinology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China.
EBioMedicine. 2021 Nov;73:103669. doi: 10.1016/j.ebiom.2021.103669. Epub 2021 Nov 5.
Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism causally influences IPF.
Two-sample Mendelian randomisation (MR) was conducted with hypothyroidism genome-wide association study (GWAS) data in the UK Biobank from 289,307 individuals (18,740 cases and 270,567 controls) and the largest GWAS summary statistics of IPF from 11,259 individuals (2,668 cases and 8,591 controls). Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. A multivariable MR based on Bayesian model averaging was further performed to evaluate whether hypothyroidism, even given several other comorbidities of IPF, remained to be the true causal one of IPF.
A positive causal effect of hypothyroidism on IPF was revealed (MR inverse-variance weighted [MR-IVW], odds ratio [OR]=1.125, 95% confidence interval [CI] 1.028-1.231; P=0.011), which was further verified in an independent validation set (MR-IVW, OR=1.229, 95% CI 1.054-1.432; P=0.008). The results were consistent from a variety of MR methods. Bidirectional analyses also indicated no reverse causation. Multivariable MR analysis showed hypothyroidism had the strongest marginal evidence (marginal inclusion probability=0.397, false discovery rate=0.025) compared with other comorbidities of IPF.
Our results illustrate the significant causal effect of hypothyroidism on IPF, which holds even given several other comorbidities of IPF. These findings may have an important insight into pathogenesis and possible future therapies of IPF.
National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and the Young Scholars Program of Shandong University.
虽然观察性研究发现甲状腺功能减退症与特发性肺纤维化（IPF）之间存在关联，但甲状腺功能减退症是否会对 IPF 产生因果影响仍不确定。
使用来自 UK Biobank 的甲状腺功能减退症全基因组关联研究（GWAS）数据（289307 人，18740 例病例和 270567 例对照）和来自 11259 人的最大 IPF GWAS 汇总统计数据（2668 例病例和 8591 例对照）进行两样本 Mendelian 随机化（MR）。使用独立验证数据集以及不同的 MR 方法（具有不同模型假设）验证了研究结果。进一步进行了基于贝叶斯模型平均的多变量 MR，以评估即使考虑到 IPF 的其他几种合并症，甲状腺功能减退症是否仍然是 IPF 的真正因果因素。
甲状腺功能减退症与 IPF 之间存在正因果关系（MR 逆方差加权[MR-IVW]，优势比[OR]=1.125，95%置信区间[CI]1.028-1.231；P=0.011），在独立验证集中进一步得到验证（MR-IVW，OR=1.229，95%CI 1.054-1.432；P=0.008）。各种 MR 方法的结果均一致。双向分析也表明不存在反向因果关系。多变量 MR 分析表明，与 IPF 的其他几种合并症相比，甲状腺功能减退症具有最强的边际证据（边际纳入概率=0.397，假发现率=0.025）。
我们的研究结果表明甲状腺功能减退症对 IPF 具有显著的因果影响，即使考虑到 IPF 的其他几种合并症也是如此。这些发现可能为 IPF 的发病机制和未来可能的治疗方法提供重要的见解。
国家自然科学基金、山东省自然科学基金和山东大学青年学者计划。
