Ma Yuchao, Feng Chang, Tang Haibo, Deng Peizhi, Li Yalan, Wang Jie, Zhu Shaihong, Zhu Liyong
Department of Cardiothoracic Surgery, The Third Xiangya Hospital, Central South University, Changsha, China.
Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.
Front Genet. 2022 Mar 11;13:821029. doi: 10.3389/fgene.2022.821029. eCollection 2022.
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. 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. Increased BMI and WC were associated with higher risk of IPF [odds ratio (OR) = 1.51, 95% confidence interval (CI) (1.22-1.87), = 1.27 × 10, and OR = 1.71, 95% CI (1.08-2.72), = 2.33 × 10, 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. 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.
目前特发性肺纤维化（IPF）的治疗通常效果不佳或治疗疗效欠佳。寻找新的风险因素对预防、延缓和治疗IPF具有重要意义。肥胖与IPF风险之间的关联尚不清楚。本研究旨在探讨不同类型肥胖在IPF风险中的作用，这为将减肥作为预防IPF的新方法提供了可能性。我们进行了一项两样本孟德尔随机化（MR）分析，以评估肥胖对IPF风险的因果效应。我们从大规模联合体（样本量从232,101到681,275不等）收集了基因决定的肥胖相关性状的汇总数据，包括体重指数（BMI）、腰围（WC）和腰臀比（WHR），以及来自一项最大的荟萃分析（包括26,68例病例）中与IPF的基因关联。总共选择了35 - 469个单核苷酸多态性作为肥胖相关性状的工具变量。我们进一步进行了多变量MR分析，以估计BMI和WC对IPF风险的独立影响。BMI和WC升高与IPF风险增加相关[比值比（OR）= 1.51，95%置信区间（CI）（1.22 - 1.87），P = 1.27 × 10，OR = 1.71，95% CI（1.08 - 2.72），P = 2.33 × 10，分别]。在重复分析中获得了BMI和WC的类似结果。随后，在多重检验校正后，只有BMI的结果得以保留，并且与加权中位数估计值显示出良好的一致性。敏感性分析表明，MR估计不存在异质性或水平多效性。进一步的多变量MR分析表明，BMI与单变量MR分析中的方向相同且幅度相似。在本研究中，几乎没有证据支持WHR对IPF风险的因果作用。基因决定的BMI证明是IPF的因果风险因素，这为探究潜在机制提供了新的见解。同时，这些结果也表明减肥可能有利于预防IPF。
