Abstract
Aims: Current idiopathic pulmonary fibrosis (IPF) therapies usually show a poor outcome or treatment efficacy. The search for new risk factors has significant implications in preventing, delaying, and treating IPF. The association between obesity and the risk of IPF is not clear. This study aimed to investigate the role of different obesity types in IPF risk, which provides the possibility of weight loss as a new approach for IPF prevention. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effect of obesity on IPF risk. We collected summary data of genetically determined obesity-related traits, including body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) from large-scale consortia (the sample size ranging from 232,101 to 681,275), and genetic association with IPF from one of the largest meta-analyses including 2,668 cases. A total of 35–469 single nucleotide polymorphisms were selected as instrumental variables for obesity-related traits. We further performed multivariable MR to estimate the independent effect of BMI and WC on the risk of IPF. Results: Increased BMI and WC were associated with higher risk of IPF [odds ratio (OR) = 1.51, 95% confidence interval (CI) (1.22–1.87), p = 1.27 × 10–4, and OR = 1.71, 95% CI (1.08–2.72), p = 2.33 × 10–2, respectively]. Similar results for the BMI and WC were obtained in the replicated analysis. Subsequently, only the result for BMI survived following the multiple testing correction and showed good consistency with the weighted median estimator. Sensitivity analyses indicated that there was no heterogeneity or horizontal pleiotropy for MR estimations. Further multivariable MR suggested that the BMI showed the same direction and similar magnitude with that in the univariable MR analysis. There was little evidence to support the causal role of WHR on the risk of IPF in this study. Conclusion: Genetically determined BMI demonstrates a causal risk for IPF, which offers a novel insight into probing potential mechanisms. Meanwhile, these results also suggest that weight loss may be beneficial to IPF prevention.
Highlights
Idiopathic pulmonary fibrosis (IPF), a kind of idiopathic interstitial pneumonia with diffuse parenchymal abnormalities and lesions, is the most frequent and severe form of fibrotic lung disease (John et al, 2020)
A total of 66 single nucleotide polymorphisms (SNPs) for body mass index (BMI) and 335 SNPs were selected for waist circumference (WC) extracted from the other independent genome-wide association studies (GWASs) summary data for further replicated analysis, with F statistics of 344.85 and 50.94, respectively
We obtained similar results in the replicated analysis, suggesting that the increased BMI and WC are associated with IPF risk [odds ratio (OR) = 1.52, 95% confidence intervals (CIs) (1.09–2.14), p = 1.49 × 10–2 and OR = 1.76, 95% CI (1.32–2.35), p = 1.25 × 10–4, respectively]
Summary
Idiopathic pulmonary fibrosis (IPF), a kind of idiopathic interstitial pneumonia with diffuse parenchymal abnormalities and lesions, is the most frequent and severe form of fibrotic lung disease (John et al, 2020). The precise factors that initiate the process of IPF are still unknown. IPF is generally considered as a consequence of environmental risk factors, including smoking (Baumgartner et al, 1997; Taskar and Coultas, 2006), viral infection (Naik and Moore, 2010), metal and wood dusts, agriculture and farming (Taskar and Coultas, 2006; Raghu et al, 2011), and interacting with genetic susceptibility (Evans et al, 2016). One possible explanation is that nonspecific injury to the epithelial barrier and pulmonary parenchyma by these risk factors initiates the disease process of IPF in susceptible individuals. These risk factors do not seem to explain very much of the progressive nature of IPF or the higher risk of pulmonary fibrosis with age. Broadening our understanding of the risk factors for IPF is of tremendous significance to its prevention, retardation, and treatment
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