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This article is the authors' final version prior to publication in American Journal of Respiratory and Critical Care Medicine, Volume 207, Issue 2, 2023, Pages 117-118.

The published version is available at Copyright © 2023 the American Thoracic Society.


RATIONALE: Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear.

OBJECTIVES: We applied Mendelian randomization (MR) analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis).

METHODS: We conducted two-sample bidirectional MR to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies (GWAS) conducted on asthma (Ncases=56,167) and GERD (Ncases=71,522). Additionally, we generated instrumental variables (IVs) for atopic dermatitis (AD) from the latest population-level GWAS meta-analysis (Ncases=22,474) and assessed their fidelity and confidence of predicting the likely causal pathway(s) leading to asthma and/or GERD.

MEASUREMENTS AND MAIN RESULTS: Applying three different methods, each method found similar magnitude of causal estimates that were directionally consistent across the sensitivity analyses. Using an inverse-variance weighted method, the largest effect size was detected for asthma predisposition to AD (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.34-1.59), followed by AD to asthma (OR, 1.34; CI, 1.24-1.45). A significant association was detected for genetically determined asthma on risk of GERD (OR, 1.06; CI, 1.03-1.09), but not genetically determined AD on GERD. In contrast, GERD equally increased risks of asthma (OR, 1.21; CI, 1.09-1.35) and AD (OR, 1.21; CI, 1.07-1.37).

CONCLUSIONS: This study uncovers previously unrecognized causal pathways that have clinical implications in European-ancestry populations: 1) asthma is a causal risk for AD; and 2) the predisposition to AD, including asthma, can arise from specific pathogenic mechanisms manifested by GERD.

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