变应性鼻炎与哮喘双向因果关系的孟德尔随机化研究

The bidirectional causal relationship between allergic rhinitis and asthma — a two-sample Mendelian randomization study

摘要

目的 基于孟德尔随机化(Mendelian randomization, MR)方法探索变应性鼻炎(allergic rhinitis, AR)与哮喘(allergic asthma, AA)之间的双向因果关系。方法 通过公共数据库纳入AR和AA患者各484 598例(GWAS数据库)、135 910例(FinnGen数据库)。设定P＜5×10^-8,R²＜0.001,kb=10 000等筛选出与AR、AA相关的合适单核苷酸多态性(single-nucleotide polymorphisms, SNPs)作为工具变量(instrumental variables, IVs)。通过计算F值,去除F＜10的弱相关SNPs。选择逆方差加权法(inverse variance weighted, IVW)作为MR分析的主要研究方法,中位加权(weighted median)、MR-Egger、加权模式(weighted mode)、简单模式(simple mode)作为补充分析方法,以优势比(odds ratio, OR)作为效应大小的评价指标,P＜0.05为差异有统计学意义。采用MR-PRESSO、MR Egger截距、Cochran's Q检验、留一法(leave one out)等对MR分析结果进行多效性、异质性及敏感性分析。MR分析的可视化结果以留一法图、散点图、漏斗图展示。结果 正向MR分析结果表明:与遗传变异相关的AR与AA之间存在显著因果关系,IVW法:OR=188 716 988.442,95% CI:8 418 864.761～4 230 273 645.508,P_ivw＜0.05,中位加权、MR-Egger、加权模式、简单模式也显示同样结果(P＜0.05)。反向因果关系表明:与遗传变异相关的AA与AR存在显著因果关系,IVW法:OR=1.027,95% CI:1.015～1.038,P_ivw＜0.001,中位加权、简单模式也显示同样结果(P＜0.05)。双向MR分析中没有证据表明SNPs存在多效性(正向:MR-Egger截距=0.021,P=0.394,反向:MR-Egger截距=0.001,P=0.966,P均＞0.05),但存在异质性(正向MR-PRESSO值=63.560,Cochran's Q=59.083,反向MR-PRESSO值=66.123,Cochran's Q=44.426,P均＜0.05)。留一法分析显示双向因果关系结果并未受到单一SNP影响(P＜0.05)。结论 基于欧洲人群的双向MR分析结果显示,AR与AA存在基因水平的双向因果关系,2种疾病互为风险因素。

Abstract

Objective To explore the bidirectional causal relationship between allergic rhinitis (AR) and allergic asthma (AA) based on the Mendelian randomization (MR) method. Methods A total of 484 598 AR patients from the GWAS database and 135 910 AA patients from the FinnGen database were included through public databases. Appropriate single-nucleotide polymorphisms (SNPs) associated with AR and AA were selected as instrumental variables (IVs) by setting criteria such as P＜5×10 ^-8, R ²＜0.001, and kb=10 000. SNPs with F-value＜10 were removed after calculating the F-value. The inverse variance weighted (IVW) method was chosen as the main approach for MR analysis, while the weighted median, MR-Egger, weighted mode, and simple mode were used as supplementary analysis methods. The odds ratio (OR) was used as the evaluation index for the effect size, and P＜0.05 was considered statistically significant. Multivariate analysis of pleiotropy, heterogeneity, and sensitivity of the MR analysis results was performed using methods such as MR-PRESSO, MR Egger intercept, Cochran's Q test, and leave-one-out method. The visualization results of the MR analysis were presented as leave-one-out plots, scatter plots, and funnel plots. Results The forward MR analysis results indicated a significant causal relationship between AR related to genetic variation and AA. By the IVW method, OR=188 716 988.442, 95% CI:8 418 864.761-4 230 273 645.508, and P _ivw＜0.05. The weighted median, MR-Egger, weighted mode, and simple mode also showed the same results (P＜0.05). The reverse causal relationship analysis showed a significant causal relationship between AA related to genetic variation and AR. By the IVW method, OR=1.027, 95%CI: 1.015-1.038, and P _ivw＜0.001. The weighted median and simple mode also showed the same results (P＜0.05). There was no evidence of pleiotropy of SNPs in the bidirectional MR analysis (forward: MR Egger intercept=0.021, P=0.394; reverse: MR Egger intercept=0.001, P=0.966, all P＞0.05), but there was heterogeneity (forward: MR-PRESSO value=63.560, Cochran's Q=59.083; reverse: MR-PRESSO value=66.123, Cochran's Q=44.426, all P＜0.05). The leave-one-out analysis showed that the bidirectional causal relationship results were not affected by a single SNP (P＜0.05). Conclusion The results of the bidirectional MR analysis based on the European population showed that there is a bidirectional causal relationship between AR and AA, and the two diseases are risk factors for each other.

关键词

孟德尔随机化 / 工具变量 / 单核苷酸多态性 / 变应性鼻炎 / 哮喘

Key words

Mendelian randomization / instrumental variable / single-nucleotide polymorphism / allergic rhinitis / asthma

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基金资助

国家自然科学基金项目(82572322)