Integrated genetic and epigenetic analyses uncover MSI2 association with allergic inflammation

The relationship between allergic and eosinophilic inflammation, either systemic or local, in allergic diseases remains unclear. We performed combined genome-wide association study (GWAS) and epigenome-wide (EWAS) for atopy and tissue eosinophilia to identify both genetic and epigenetic signatures b...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology 2021-04, Vol.147 (4), p.1453-1463
Main Authors: Kim, Kyung Won, Park, Sang-Cheol, Cho, Hyung-Ju, Jang, Haerin, Park, Jaehyun, Shim, Hyo Sup, Kim, Eun Gyul, Kim, Mi Na, Hong, Jung Yeon, Kim, Yoon Hee, Lee, Sanghun, Weiss, Scott T., Kim, Chang-Hoon, Won, Sungho, Sohn, Myung Hyun
Format: Article
Language:English
Subjects:
Allergic diseases
Asthma
Atopy
Blood diseases
Deoxyribonucleic acid
DNA
DNA methylation
Eosinophilia
epigenetic
Epigenetics
Gene expression
Gene regulation
genetic
Genetic analysis
Genome-wide association studies
Genomes
GWAS
Health risk assessment
Hypersensitivity
Immune response
Inflammation
Leukocytes (eosinophilic)
methylation
Phenotypes
Quality control
RNA-binding protein
Single-nucleotide polymorphism
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Summary:The relationship between allergic and eosinophilic inflammation, either systemic or local, in allergic diseases remains unclear. We performed combined genome-wide association study (GWAS) and epigenome-wide (EWAS) for atopy and tissue eosinophilia to identify both genetic and epigenetic signatures between systemic and local allergic inflammation, and to capture global patterns of gene regulation. We included 126 subjects for atopy analysis and 147 for tissue eosinophilia analysis, as well as 18 normal nasal tissue samples. We identified differentially methylated positions (DMPs) and genes associated with atopy and tissue eosinophilia. Furthermore, we performed mendelian randomization analysis and penalized regression along with replication in an independent cohort. EWAS identified genes, including Musashi RNA binding protein 2 (MSI2), associated with atopy, which contained enriched DMPs that genetically affect atopy. A direct association was observed between MSI2 single-nucleotide polymorphisms and atopy, as was a causal effect of changes in MSI2 expression and methylation on atopy, which was replicated in a Costa Rican population. Regarding tissue eosinophilia, EWAS identified genes with enriched DMPs directly contributing to tissue eosinophilia at the gene level, including CAMK1D. The gene ontology terms of the identified genes for both phenotypes encompassed immune-related terms. EWAS combined with GWAS identified novel candidate genes, especially the methylation of MSI2, contributing to systemic allergic inflammation. Certain genes displayed a greater association with either systemic or local allergic inflammation; however, it is expected that a harmonized effect of these genes influences immune responses. [Display omitted]
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2020.06.040