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Title: | The ERBB2 Exonic Variant Pro1170Ala Modulates Mitogen-Activated Protein Kinase Signaling Cascades and Associates with Allergic Asthma | Authors: | Sio, Yang Yie Gan, Wei Liang Ng, Wing Shan Matta, Sri Anusha Say, Yee-How Teh, Keng Foo Wong, Yi Ru Rawanan Shah, Smyrna Moti Reginald, Kavita Chew, Fook Tim |
Keywords: | Allergy Allergic asthma Asthma genetics ERBB2 Mitogen-activated protein kinase |
Issue Date: | 19-Jun-2023 | Publisher: | S. Karger AG | Citation: | Sio, Yang Yie, Gan, Wei Liang, Ng, Wing Shan, Matta, Sri Anusha, Say, Yee-How, Teh, Keng Foo, Wong, Yi Ru, Rawanan Shah, Smyrna Moti, Reginald, Kavita, Chew, Fook Tim (2023-06-19). The ERBB2 Exonic Variant Pro1170Ala Modulates Mitogen-Activated Protein Kinase Signaling Cascades and Associates with Allergic Asthma. International Archives of Allergy and Immunology. ScholarBank@NUS Repository. https://doi.org/10.1159/000530960 | Rights: | Attribution-NonCommercial 4.0 International | Abstract: | Introduction: Previous studies have indicated the ERBB2 genetic variants in the 17q12 locus might be associated with asthma; however, the functional effects of these variants on asthma risk remain inconclusive. This study aimed to characterize the functional roles of asthma-associated ERBB2 single nucleotide polymorphisms (SNPs) in asthma pathogenesis by performing genetic association and functional analysis studies. Methods: This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). Genotype-phenotype associations were assessed by performing a genotyping assay on n = 4,348 ethnic Chinese individuals from the SMCSGES cohort. The phosphorylation levels of receptors and signaling proteins in the MAPK signaling cascades, including ErbB2, EGFR, and ERK1/2, were compared across the genotypes of asthma-associated SNPs through in vitro and ex vivo approaches. Results: The ERBB2 tag-SNP rs1058808 was significantly associated with allergic asthma, with the allele “G” identified as protective against the disease (adjusted logistic p = 6.56 × 10?9, OR = 0.625, 95% CI: 0.544–0.718). The allele “G” of rs1058808 resulted in a Pro1170Ala mutation that results in lower phosphorylation levels of ErbB2 in HaCat cells (p < 0.001), whereas the overall ERBB2 mRNA expression and the phosphorylation levels of EGFR remained unaffected. In the SMCSGES cohort, individuals carrying the genotype “GG” of rs1058808 had lower phosphorylated ERK1/2 proteins in the MAPK signaling cascade. A lower phosphorylation level of ERK1/2 was also associated with reduced asthma risk. Conclusions: The present findings highlighted the involvement of a functional exonic variant of ERBB2 in asthma development via modulating the MAPK signaling cascade. | Source Title: | International Archives of Allergy and Immunology | URI: | https://scholarbank.nus.edu.sg/handle/10635/243791 | ISSN: | 1018-2438 1423-0097 |
DOI: | 10.1159/000530960 | Rights: | Attribution-NonCommercial 4.0 International |
Appears in Collections: | Staff Publications Elements |
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