Integrated genetic and epigenetic analyses uncover MSI2 association with allergic inflammation

Kyung Won Kim, Sang Cheol Park, Hyung Ju Cho, Haerin Jang, Jaehyun Park, Hyo Sup Shim, Eun Gyul Kim, Mi Na Kim, Jung Yeon Hong, Yoon Hee Kim, Sanghun Lee, Scott T. Weiss, Chang Hoon Kim, Sungho Won, Myung Hyun Sohn

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The relationship between allergic and eosinophilic inflammation, either systemic or local, in allergic diseases remains unclear. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusAccepted/In press - 2020

Bibliographical note

Funding Information:
Supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (grants NRF-2015R1D1A1A01061217, NRF-2018R1A5A2025079, and NRF-2020R1A2B5B02001713); the Bio-Synergy Research Project (grant NRF-2017M3A9C4065964) of the Ministry of Science, ICT and Future Planning through the NRF, the Bio & Medical Technology Development Program of the NRF funded by the Ministry of Science, ICT & Future Planning (grant NRF-2016M3A9D5A01952414); an NRF grant funded by the Korea government through the Ministry of Science, ICT & Future Planning (grant 2019R1A2C1089841); and grant P01 HL132825 from the National Heart, Lung and Blood Institute, National Institutes of Health (to S.T. Weiss).

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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