牙周炎与哮喘的因果关系：一项两样本孟德尔随机化研究

Causal relationship between periodontitis and asthma: a two-sample Mendelian randomization study

摘要

目的 通过双样本孟德尔随机化法（Mendelian randomization，MR）探究牙周炎与哮喘的双向因果关系，为牙周炎和哮喘的病因探索和防治措施制定提供基础。方法 使用公开发布的欧洲人种的牙周炎（n = 34 615）与哮喘（n = 408 422）的全基因组关联研究（genome-wide association studies，GWAS）统计数据进行了两样本双向孟德尔随机化分析。以逆方差加权法（inverse variance weighted，IVW）作为主要MR分析方法来估计牙周炎与哮喘之间的双向因果效应，同时采用加权中位数法（weighted median，WM）、MR-Egger回归法、最大似然法（maximum likelihood）和孟德尔随机化稳健调整特征评分法（Mendelian randomization robust adjusted profile score，MR-RAPS）作为补充分析，并通过Cochran's Q检验、孟德尔随机化多效性残差与离群值检测（Mendelian randomization pleiotropy residual sum and outlier，MR-PRESSO）和留一法进行敏感性分析。结果 最终分别有12个和43个单核苷酸多态性（single nucleotide polymorphism，SNP）被纳入作为牙周炎和哮喘的工具变量。IVW、WM、MR-Egger回归、最大似然法和MR-RAPS的结果表明，在欧洲人群中，牙周炎对哮喘发病无因果关系（IVW：OR=1.003，95%CI=0.973-1.035，P = 0.828；WM：OR=0.990，95%CI=0.951-1.031，P = 0.641；MR-Egger回归：OR=0.988，95%CI=0.960-1.028，P = 0.573；最大似然法：OR=1.003，95%CI=0.972-1.035，P = 0.834；MR-RAPS：OR=1.002，95%CI=0.970-1.036，P = 0.890）；哮喘对牙周炎也无因果关系（IVW：OR=1.021，95%CI=0.938-1.111，P=0.633；WM：OR=1.011，95%CI=0.894-1.142，P = 0.866；MR-Egger回归：OR=1.042，95%CI=0.824-1.319，P = 0.731；最大似然法：OR=1.021，95%CI=0.938-1.112，P = 0.631；MR-RAPS：OR=1.017，95%CI=0.931-1.110，P = 0.713）。Cochran's Q检验表明纳入的工具变量之间不具有异质性，MR-PRESSO检验显示不存在水平多效性，留一法也未发现离群SNP。结论 基于欧洲人群遗传数据的MR研究表明，牙周炎与哮喘发病之间不存在双向的因果关系。

Abstract

Objective To explore the bidirectional causal relationships between periodontitis and asthma using the two-sample Mendelian randomization (MR) method to provide a basis for exploring the etiology and formulating preventive and therapeutic measures of periodontitis and asthma. Methods We performed two-sample bidirectional Mendelian randomization analysis using publicly released European genome-wide association studies (GWAS) statistics for periodontitis (n = 34 615) and asthma (n = 408 422). The inverse variance weighted (IVW) method was employed as the main approach to estimate the bidirectional causal relationships between periodontitis and asthma. In addition, weighted median (WM), MR-Egger regression, maximum likelihood, and Mendelian randomization robust adjusted profile score (MR-RAPS) were used as supplementary analyses. Sensitivity analyses were conducted using Cochran's Q test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis. Results A total of 12 and 43 single-nucleotide polymorphisms (SNPs) were included as instrumental variables for periodontitis and asthma, respectively. The results of IVW, WM, MR-Egger regression, maximum likelihood, and MR-RAPS showed that periodontitis was not causally related to the risk of asthma (IVW: OR: 1.003, 95% CI: 0.973-1.035, P = 0.828, WM: OR: 0.990, 95% CI: 0.951-1.031, P = 0.641; MR-Egger regression: OR: 0.988, 95% CI: 0.960-1.028, P = 0.573; maximum likelihood: OR: 1.003, 95% CI: 0.972-1.035, P = 0.834; MR-RAPS: OR: 1.002, 95% CI: 0.970-1.036, P = 0.890) among the European population, and no causal effect of asthma on periodontitis was found (IVW: OR: 1.021, 95% CI: 0.938-1.111, P = 0.633, WM: OR: 1.011, 95% CI: 0.894-1.142, P = 0.866; MR-Egger regression: OR: 1.042, 95% CI: 0.824-1.319, P = 0.731; maximum likelihood: OR: 1.021, 95% CI: 0.938-1.112, P = 0.631; MR-RAPS: OR: 1.017, 95% CI: 0.931-1.110, P = 0.713) among the European population. Cochran's Q test showed no heterogeneity among the included instrumental variables, MR-PRESSO test found no horizontal pleiotropy, and the leave-one-out method did not identify outlier SNPs. Conclusion The results of this study, based on European genetic data, do not support a bidirectional causal association between periodontitis and asthma in the European population.

关键词

牙周炎 / 哮喘 / 孟德尔随机化 / 全基因组关联分析 / 单核苷酸多态性 / 因果关联 / 双向因果 / 工具变量 / 敏感性分析

Key words

periodontitis / asthma / Mendelian randomization / genome-wide-association study / single nucleotide polymorphism / causal association / bidirectional casual association / instrumental variable / sensitivity analysis

Author summay

陈麒伟，住院医师，在读硕士研究生，Email：[e-mail]