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Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis

BACKGROUND: Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism causally influences IPF. METHODS: Two-sample Mendelian randomisation (MR) was conducted with hypothyroidism genome-wide a...

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Autores principales: Zhang, Yanan, Zhao, Meng, Guo, Ping, Wang, Yanjun, Liu, Lu, Zhao, Jinghua, Gao, Ling, Yuan, Zhongshang, Xue, Fuzhong, Zhao, Jiajun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586742/
https://www.ncbi.nlm.nih.gov/pubmed/34749302
http://dx.doi.org/10.1016/j.ebiom.2021.103669
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author Zhang, Yanan
Zhao, Meng
Guo, Ping
Wang, Yanjun
Liu, Lu
Zhao, Jinghua
Gao, Ling
Yuan, Zhongshang
Xue, Fuzhong
Zhao, Jiajun
author_facet Zhang, Yanan
Zhao, Meng
Guo, Ping
Wang, Yanjun
Liu, Lu
Zhao, Jinghua
Gao, Ling
Yuan, Zhongshang
Xue, Fuzhong
Zhao, Jiajun
author_sort Zhang, Yanan
collection PubMed
description BACKGROUND: Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism causally influences IPF. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and the Young Scholars Program of Shandong University.
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spelling pubmed-85867422021-11-19 Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis Zhang, Yanan Zhao, Meng Guo, Ping Wang, Yanjun Liu, Lu Zhao, Jinghua Gao, Ling Yuan, Zhongshang Xue, Fuzhong Zhao, Jiajun EBioMedicine Research paper BACKGROUND: Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism causally influences IPF. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and the Young Scholars Program of Shandong University. Elsevier 2021-11-05 /pmc/articles/PMC8586742/ /pubmed/34749302 http://dx.doi.org/10.1016/j.ebiom.2021.103669 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Zhang, Yanan
Zhao, Meng
Guo, Ping
Wang, Yanjun
Liu, Lu
Zhao, Jinghua
Gao, Ling
Yuan, Zhongshang
Xue, Fuzhong
Zhao, Jiajun
Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis
title Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis
title_full Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis
title_fullStr Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis
title_full_unstemmed Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis
title_short Mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis
title_sort mendelian randomisation highlights hypothyroidism as a causal determinant of idiopathic pulmonary fibrosis
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586742/
https://www.ncbi.nlm.nih.gov/pubmed/34749302
http://dx.doi.org/10.1016/j.ebiom.2021.103669
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