Functional Polymorphisms Regulate FOXO1 Transcript Expression and Contribute to the Risk and Symptom Severity of HDM-Induced Allergic Rhinitis

Yang Yie Sio; Kefan Du; Terence Yin Weng Lam; Yee-How Say; Kavita Reginald; Fook Tim Chew

doi:10.1159/000540686

Functional Polymorphisms Regulate FOXO1 Transcript Expression and Contribute to the Risk and Symptom Severity of HDM-Induced Allergic Rhinitis

Int Arch Allergy Immunol. 2024 Aug 29:1-11. doi: 10.1159/000540686. Online ahead of print.

Authors

Yang Yie Sio¹, Kefan Du², Terence Yin Weng Lam², Yee-How Say^{2

3

4}, Kavita Reginald⁴, Fook Tim Chew²

Affiliations

¹ Department of Biological Sciences, National University of Singapore, Singapore, Singapore, dbssioy@nus.edu.sg.
² Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
³ Department of Biomedical Science, Faculty of Science, Universiti Tunku Abdul Rahman (UTAR) Kampar Campus, Kampar, Malaysia.
⁴ Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Subang Jaya, Malaysia.

PMID: 39208774
DOI: 10.1159/000540686

Abstract

Introduction: FOXO1 plays an important role in regulating immune processes that contribute to allergic inflammation; however, genetic variants influencing FOXO1 expression in AR pathogenesis remains unclear. This study aimed to investigate the functional effect of FOXO1 single nucleotide polymorphisms (SNPs) on AR development 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). We assessed the associations of FOXO1 transcript expression levels in peripheral blood mononuclear cells (PBMC) with AR phenotype, total nasal symptom score (TNSS), and SNP genotype in a sub-cohort of n = 658 individuals from the SMCSGES population. Associations of FOXO1 SNPs with AR were assessed in a cohort of n = 5,072 individuals from the SMCSGES population. In vitro promoter luciferase assay was used to evaluate the effect of AR-associated SNPs on FOXO1 promoter activity.

Results: FOXO1 transcript expression in PBMC was significantly associated with the risk of AR (p < 0.05) and TNSS among AR patients (p < 0.0001). We identified a significant association between tag-SNPs rs9549246 and FOXO1 transcript expression in PBMC from the SMCSGES sub-cohort and the multiethnic eQTLGen consortium (false discovery rate-adjusted p < 0.05). The minor allele "A" of tag-SNP rs9549246 was significantly associated with a higher risk of AR (p = 0.04422, odds ratio = 1.21, 95% confidence interval = 1.01-1.45) in the SMCSGES genotyping cohort (n = 5,072). In vitro luciferase assay showed the minor allele "A" of rs35594717 (tagged by rs9549246) was significantly associated with a higher FOXO1 promoter activity (p < 0.05).

Conclusion: FOXO1 transcript expression in PBMC has a strong association with the risk and symptom severity of AR. Genetic variants tagged by rs9549246 were shown to affect the expression of FOXO1 and contribute to the development of AR in the SMCSGES population.

Keywords: Allergic rhinitis; Allergy; FOXO1; Peripheral blood mononuclear cell; Single nucleotide polymorphism.