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

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 rateadjusted 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. © 2024 The Author(s).