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

Abstract

<b><i>Introduction:</i></b> <i>FOXO1</i> plays an important role in regulating immune processes that contribute to allergic inflammation; however, genetic variants influencing <i>FOXO1</i> expression in AR pathogenesis remains unclear. This study aimed to investigate the functional effect of <i>FOXO1</i> single nucleotide polymorphisms (SNPs) on AR development by performing genetic association and functional analysis studies. <b><i>Methods:</i></b> This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). We assessed the associations of <i>FOXO1</i> 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 <i>n</i> = 658 individuals from the SMCSGES population. Associations of <i>FOXO1</i> SNPs with AR were assessed in a cohort of <i>n</i> = 5,072 individuals from the SMCSGES population. In vitro promoter luciferase assay was used to evaluate the effect of AR-associated SNPs on <i>FOXO1</i> promoter activity. <b><i>Results:</i></b> <i>FOXO1</i> transcript expression in PBMC was significantly associated with the risk of AR (<i>p</i> &lt; 0.05) and TNSS among AR patients (<i>p</i> &lt; 0.0001). We identified a significant association between tag-SNPs rs9549246 and <i>FOXO1</i> transcript expression in PBMC from the SMCSGES sub-cohort and the multiethnic eQTLGen consortium (false discovery rate-adjusted <i>p</i> &lt; 0.05). The minor allele “A” of tag-SNP rs9549246 was significantly associated with a higher risk of AR (<i>p</i> = 0.04422, odds ratio = 1.21, 95% confidence interval = 1.01–1.45) in the SMCSGES genotyping cohort (<i>n</i> = 5,072). In vitro luciferase assay showed the minor allele “A” of rs35594717 (tagged by rs9549246) was significantly associated with a higher <i>FOXO1</i> promoter activity (<i>p</i> &lt; 0.05). <b><i>Conclusion:</i></b> <i>FOXO1</i> 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 <i>FOXO1</i> and contribute to the development of AR in the SMCSGES population.