Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8586742 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPrevious observational studies have investigated the association between endocrine and metabolic factors and idiopathic pulmonary fibrosis (IPF), yet have produced inconsistent results. Therefore, it is imperative to employ the Mendelian randomization (MR) analysis method to conduct a more comprehensive investigation into the impact of endocrine and metabolic factors on IPF.MethodsThe instrumental variables (IVs) for 53 endocrine and metabolic factors were sourced from publicly accessible genome-wide association study (GWAS) databases, with GWAS summary statistics pertaining to IPF employed as the dependent variables. Causal inference analysis encompassed the utilization of three methods: inverse-variance weighted (IVW), weighted median (WM), and MR-Egger. Sensitivity analysis incorporated the implementation of MR-PRESSO and leave-one-out techniques to identify potential pleiotropy and outliers. The presence of horizontal pleiotropy and heterogeneity was evaluated through the MR-Egger intercept and Cochran's Q statistic, respectively.ResultsThe IVW method results reveal correlations between 11 traits and IPF. After correcting for multiple comparisons, seven traits remain statistically significant. These factors include: "Weight" (OR= 1.44; 95% CI: 1.16, 1.78; P=8.71×10-4), "Body mass index (BMI)" (OR= 1.35; 95% CI: 1.13, 1.62; P=1×10-3), "Whole body fat mass" (OR= 1.40; 95% CI: 1.14, 1.74; P=1.72×10-3), "Waist circumference (WC)" (OR= 1.54; 95% CI: 1.16, 2.05; P=3.08×10-3), "Trunk fat mass (TFM)" (OR=1.35; 95% CI: 1.10,1.65; P=3.45×10-3), "Body fat percentage (BFP)" (OR= 1.55; 95% CI: 1.15,2.08; P=3.86×10-3), "Apoliprotein B (ApoB)" (OR= 0.78; 95% CI: 0.65,0.93; P=5.47×10-3). Additionally, the sensitivity analysis results confirmed the reliability of the MR results.ConclusionThe present study identified causal relationships between seven traits and IPF. Specifically, ApoB exhibited a negative impact on IPF, while the remaining six factors demonstrated a positive impact. These findings offer novel insights into the underlying etiopathological mechanisms associated with IPF.

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