Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease
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.
Ahn, Kwangmi; Penn, Raymond B.; Rattan, Satish; Panettieri, Reynold A.; Voight, Benjamin F.; and An, Steven S., "Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease" (2023). Division of Gastroenterology and Hepatology Faculty Papers. Paper 87.
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Available for download on Monday, January 15, 2024
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 https://doi.org/10.1164/rccm.202205-0951OC. Copyright © 2023 the American Thoracic Society.