Mechanisms of allergy/immunology
Integrated genetic and epigenetic analyses uncover MSI2 association with allergic inflammation

https://doi.org/10.1016/j.jaci.2020.06.040Get rights and content

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.

Section snippets

Methods

Fig 1 provides a schematic representation of the combined GWAS and EWAS analyses for atopy and tissue eosinophilia herein. Among the 134 enrolled patients, samples from 108 and 129 patients were used for atopy analyses and eosinophilia analyses, respectively. Furthermore, we used 18 normal nasal tissue samples for these analyses. Clinical definitions of atopy and tissue eosinophilia and detailed sample compositions are provided in the Online Repository materials for this article (available at //jacionline.org

Subjects’ characteristics

Atopy analysis was performed for 126 subjects, and tissue eosinophilia analysis was performed for 147 subjects, including 18 subjects with normal tissues; their clinical characteristics are summarized in Table I.

Differences in DNA methylation in atopy and tissue eosinophilia

To investigate the airway epigenetic signatures associated with atopy and tissue eosinophilia, we identified differences in methylation between atopy and nonatopy and between eosinophilia and noneosinophilia in the nasal polyp. For more than 850,000 methylation probes across the genome,

Discussion

Our study describes airway epigenetic signatures associated with atopy and tissue eosinophilia through an integrative approach, including DMP identification and functional analyses with DMP-enriched genes, meQTL analysis, instrumental variable analysis, and variance estimation, along with replication in an independent cohort. This study revealed a novel candidate gene, MSI2, associated with atopy through genetic-epigenetic interactions and another candidate gene, CAMK1D, associated with tissue

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    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).

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

    ∗

    These authors contributed equally to this work.

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