Plasma genome-wide mendelian randomization identifies potentially causal genes in idiopathic pulmonary fibrosis.

IF 5.8 2区医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-18 DOI:10.1186/s12931-024-03008-5

Kun Zhang, Puyu Shi, Anqi Li, Jiejun Zhou, Mingwei Chen

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Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with a very poor prognosis. Existing drugs for the treatment of IPF are still insufficient. Therefore, there is still a need to explore new drug targets for preventing and treating IPF.

Methods: We included quantitative trait loci (QTL) for genes, DNA methylation, and proteins in plasma, as well as the summary statistics for IPF. Genetic variants located within 500 kb of the gene and strongly associated with plasma exposure were used as instrumental variables. The causal association between plasma exposures and IPF was primarily estimated using summary-data-based Mendelian randomization (SMR) analysis. Five other MR methods and sensitivity analyses were employed to validate the SMR results. Bayesian tests for colocalization between QTL and IPF risk loci further strengthen the MR results.

Results: We identified three genes and five DNA methylation sites causally associated with IPF by SMR analysis, validation of MR analysis, sensitivity analysis, and colocalization analysis. BTRC and LINC01252 were negatively associated with IPF risk (OR: 0.30, 95% CI: 0.17-0.54, FDR_SMR = 0.029; OR: 0.85, 95% CI: 0.78-0.92, FDR_SMR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64-4.12, FDR_SMR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08-1.24, FDR_SMR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12-1.36, FDR_SMR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98-5.08, FDR_SMR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10-1.30, FDR_SMR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11-0.45, FDR_SMR = 0.013) was negatively correlated with the risk of IPF.

Conclusions: This study demonstrated that genetically determined plasma levels of the BTRC, RIPK4, and LINC01252 genes, as well as methylation levels of cg00045227 (OR8U8), cg00577578 (GBAP1), cg07163735 (MAPT), cg14222479 (ARPM1), and cg19263494 (PMF1), have causal influences on the risk of IPF.

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血浆全基因组泯灭随机化确定了特发性肺纤维化的潜在致病基因。

背景：特发性肺纤维化（IPF特发性肺纤维化（IPF）是一种复杂的肺部疾病，预后极差。现有治疗 IPF 的药物仍然不足。因此，仍有必要探索预防和治疗 IPF 的新药物靶点：我们纳入了血浆中基因、DNA甲基化和蛋白质的定量性状位点（QTL），以及 IPF 的汇总统计数据。位于基因 500 kb 范围内且与血浆暴露密切相关的基因变异被用作工具变量。血浆暴露与 IPF 之间的因果关系主要通过基于汇总数据的孟德尔随机（SMR）分析进行估计。还采用了其他五种 MR 方法和敏感性分析来验证 SMR 结果。QTL与IPF风险基因座之间的贝叶斯检验进一步加强了MR结果：结果：通过SMR分析、MR分析验证、敏感性分析和共定位分析，我们确定了与IPF有因果关系的3个基因和5个DNA甲基化位点。BTRC和LINC01252与IPF风险呈负相关（OR：0.30，95% CI：0.17-0.54，FDRSMR = 0.029；OR：0.85，95% CI：0.78-0.92，FDRSMR = 0.043），RIPK4 与 IPF 风险正相关（OR：2.60，95% CI：1.64-4.12，FDRSMR = 0.031）。cg00045227（OR8U8，OR：1.16，95% CI：1.08-1.24，FDRSMR = 0.010）、cg00577578（GBAP1，OR：1.23，95% CI：1.12-1.36，FDRSMR = 0.014）、cg14222479（ARPM1，OR：3.17，95% CI：1.98-5.08，FDRSMR = 0.001）和 cg19263494（PMF1，OR：1.20，95% CI：1.10-1.30，FDRSMR = 0.012）与 IPF 风险呈正相关，而 cg07163735（MAPT，OR：0.22，95% CI：0.11-0.45，FDRSMR = 0.013）与 IPF 风险呈负相关：该研究表明，由基因决定的 BTRC、RIPK4 和 LINC01252 基因的血浆水平，以及 cg00045227 (OR8U8)、cg00577578 (GBAP1)、cg07163735 (MAPT)、cg14222479 (ARPM1) 和 cg19263494 (PMF1) 的甲基化水平对 IPF 的风险有因果影响。

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来源期刊

Respiratory Research RESPIRATORY SYSTEM-

CiteScore

9.70

自引率

1.70%

发文量

314

审稿时长

4-8 weeks

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.