慢性咳嗽与胃食管反流病：双向两样本孟德尔随机化研究

doi:10.3877/cma.j.issn.2095-8765.2023.02.001

目的

利用孟德尔随机化分析来探索胃食管反流病（GERD）是否与慢性咳嗽存在因果关系。

方法

从两个公开的全基因组关联研究数据库（GWAS）中提取了与慢性咳嗽强烈相关的工具变量，并从欧洲分子生物学实验室数据库中提取了与GERD强烈相关的工具变量。主要采用逆方差加权法来评估慢性咳嗽与GERD之间的因果关系。

结果

发现GERD会增加慢性咳嗽发生的风险，两者存在因果关系（OR=1.03, P=1.70×10⁻⁷；OR=1.03, P=2.42×10⁻⁵）；然而，慢性咳嗽与GERD发生风险无相关性（P>0.05）。并且未观察到显著的多效性和异质性。

结论

GERD会增加慢性咳嗽的发生风险。

关键词: 胃食管反流病, 慢性咳嗽, 孟德尔随机化

Objective

Mendelian randomization was used to explore whether there is a causal relationship between gastroesophageal reflux disease (GERD) and chronic cough.

Methods

We extracted independent genetic variants strongly associated with chronic cough from two published genome-wide association studies (GWAS) and summary statistics for GERD from a GWAS analysis in the European Molecular Biology Laboratory. The causal relationship between chronic cough and GERD was assessed using inverse variance weighted (IVW) as main estimation.

Results

GERD was observed for causal association with increased risk for chronic cough for IVW analysis for applying two GWAS data (P=1.70×10⁻⁷ and P=2.42×10⁻⁵, respectively). However, there was no association of genetically predicted chronic cough with GERD (all P>0.05). None evidence of significant pleiotropy and heterogeneity was observed.

Conclusion

There was a causal relationship between GERD and increased risk of chronic cough.

Key words: Gastroesophageal reflux disease, Chronic cough, Mendelian randomization

图1 孟德尔随机化流程图注：GERD为胃食管反流病

表1 欧洲个体中GERD和慢性咳嗽之间关系的双样本孟德尔随机效应结果

暴露	结局	MR	SNP数	OR (95%CI)	P 值
胃食管反流病	慢性咳嗽	IVW	88 ^a	1.03 (1.02~1.04)	1.70×10^-7
		MR Egger	88^a	0.99 (0.93~1.06)	0.87
		Weighted median	88^a	1.03 (1.02~1.05)	2.42×10^-5
		Weighted mode	88^a	1.04 (1.00~1.07)	0.06
		Simple mode	88^a	1.04 (1.00~1.08)	0.07
		IVW	86^b	1.28 (1.13~1.44)	8.88×10^-5
		MR Egger	86^b	0.62 (0.30~1.28)	0.20
		Weighted median	86^b	1.29 (1.07~1.54)	7.28×10^-3
		Weighted mode	86^b	1.35 (0.87~2.07)	0.18
		Simple mode	86^b	1.42 (0.90~2.22)	0.13
慢性咳嗽	胃食管反流病	IVW	7^a	1.76 (0.70~4.43)	0.23
		MR Egger	7^a	0.42 (0.01~13.34)	0.64
		Weighted median	7^a	1.13 (0.60~2.13)	0.75
		Weighted mode	7^a	1.11 (0.54~2.27)	0.78
		Simple mode	7^a	1.14 (0.55~2.36)	0.74
		IVW	2^b	1.03 (0.96~1.11)	0.45

表1 欧洲个体中GERD和慢性咳嗽之间关系的双样本孟德尔随机效应结果

暴露	结局	MR	SNP数	OR (95%CI)	P 值
胃食管反流病	慢性咳嗽	IVW	88 ^a	1.03 (1.02~1.04)	1.70×10^-7
		MR Egger	88^a	0.99 (0.93~1.06)	0.87
		Weighted median	88^a	1.03 (1.02~1.05)	2.42×10^-5
		Weighted mode	88^a	1.04 (1.00~1.07)	0.06
		Simple mode	88^a	1.04 (1.00~1.08)	0.07
		IVW	86^b	1.28 (1.13~1.44)	8.88×10^-5
		MR Egger	86^b	0.62 (0.30~1.28)	0.20
		Weighted median	86^b	1.29 (1.07~1.54)	7.28×10^-3
		Weighted mode	86^b	1.35 (0.87~2.07)	0.18
		Simple mode	86^b	1.42 (0.90~2.22)	0.13
慢性咳嗽	胃食管反流病	IVW	7^a	1.76 (0.70~4.43)	0.23
		MR Egger	7^a	0.42 (0.01~13.34)	0.64
		Weighted median	7^a	1.13 (0.60~2.13)	0.75
		Weighted mode	7^a	1.11 (0.54~2.27)	0.78
		Simple mode	7^a	1.14 (0.55~2.36)	0.74
		IVW	2^b	1.03 (0.96~1.11)	0.45

图2 各数据库中GERD对慢性咳嗽效应的MR分析散点图注：X轴表示来自不同结果数据库与慢性咳嗽相关的工具变量，Y轴表示与GERD相关的工具变量。黑点表示工具变量对MR分析产生的效应。GERD为胃食管反流病；MR为孟德尔随机化；SNP为单核苷酸多态性

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Chronic cough and gastroesophageal reflux disease: a bidirectional two-sample mendelian randomization study

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Chronic cough and gastroesophageal reflux disease: a bidirectional two-sample mendelian randomization study