血浆全基因组孟德尔随机化分析鉴定特发性肺纤维化中的潜在因果基因。

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

机构信息

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277#, Yanta West Road, Xi'an, Shaanxi Province, 710061, China.

出版信息

Respir Res. 2024 Oct 18;25(1):379. doi: 10.1186/s12931-024-03008-5.

DOI:10.1186/s12931-024-03008-5

PMID:39425105

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11490078/

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 = 0.029; OR: 0.85, 95% CI: 0.78-0.92, FDR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64-4.12, FDR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08-1.24, FDR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12-1.36, FDR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98-5.08, FDR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10-1.30, FDR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11-0.45, FDR = 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.

摘要

背景

特发性肺纤维化（IPF）是一种预后非常差的复杂肺部疾病。现有的 IPF 治疗药物仍然不足。因此，仍然需要探索新的药物靶点来预防和治疗 IPF。

方法

我们纳入了基因、DNA 甲基化和血浆蛋白的定量性状基因座（QTL），以及 IPF 的汇总统计数据。位于基因 500kb 以内且与血浆暴露强相关的遗传变异被用作工具变量。使用基于汇总数据的孟德尔随机化（SMR）分析主要估计血浆暴露与 IPF 之间的因果关联。采用其他五种 MR 方法和敏感性分析来验证 SMR 结果。QTL 和 IPF 风险位点之间的共定位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，我们确定了三个基因和五个与 IPF 相关的 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，FDR = 0.029；OR：0.85，95%CI：0.78-0.92，FDR = 0.043），而 RIPK4 与 IPF 风险呈正相关（OR：2.60，95%CI：1.64-4.12，FDR = 0.031）。cg00045227（OR8U8，OR：1.16，95%CI：1.08-1.24，FDR = 0.010）、cg00577578（GBAP1，OR：1.23，95%CI：1.12-1.36，FDR = 0.014）、cg14222479（ARPM1，OR：3.17，95%CI：1.98-5.08，FDR = 0.001）和 cg19263494（PMF1，OR：1.20，95%CI：1.10-1.30，FDR = 0.012）与 IPF 风险呈正相关，而 cg07163735（MAPT，OR：0.22，95%CI：0.11-0.45，FDR = 0.013）与 IPF 风险呈负相关。

结论

本研究表明，BTRC、RIPK4 和 LINC01252 基因的遗传决定血浆水平以及 cg00045227（OR8U8）、cg00577578（GBAP1）、cg07163735（MAPT）、cg14222479（ARPM1）和 cg19263494（PMF1）的 DNA 甲基化水平与 IPF 风险存在因果关系。