Yang Yie SioKefan DuTerence Yin Weng LamYee-How SayKavita ReginaldFook Tim Chew2024-12-262024-12-262024-08-2910.1159/000540686https://dspace-cris.utar.edu.my/handle/123456789/8108<jats:p>&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; &lt;i&gt;FOXO1&lt;/i&gt; plays an important role in regulating immune processes that contribute to allergic inflammation; however, genetic variants influencing &lt;i&gt;FOXO1&lt;/i&gt; expression in AR pathogenesis remains unclear. This study aimed to investigate the functional effect of &lt;i&gt;FOXO1&lt;/i&gt; single nucleotide polymorphisms (SNPs) on AR development by performing genetic association and functional analysis studies. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). We assessed the associations of &lt;i&gt;FOXO1&lt;/i&gt; 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 &lt;i&gt;n&lt;/i&gt; = 658 individuals from the SMCSGES population. Associations of &lt;i&gt;FOXO1&lt;/i&gt; SNPs with AR were assessed in a cohort of &lt;i&gt;n&lt;/i&gt; = 5,072 individuals from the SMCSGES population. In vitro promoter luciferase assay was used to evaluate the effect of AR-associated SNPs on &lt;i&gt;FOXO1&lt;/i&gt; promoter activity. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; &lt;i&gt;FOXO1&lt;/i&gt; transcript expression in PBMC was significantly associated with the risk of AR (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.05) and TNSS among AR patients (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.0001). We identified a significant association between tag-SNPs rs9549246 and &lt;i&gt;FOXO1&lt;/i&gt; transcript expression in PBMC from the SMCSGES sub-cohort and the multiethnic eQTLGen consortium (false discovery rate-adjusted &lt;i&gt;p&lt;/i&gt; &amp;lt; 0.05). The minor allele “A” of tag-SNP rs9549246 was significantly associated with a higher risk of AR (&lt;i&gt;p&lt;/i&gt; = 0.04422, odds ratio = 1.21, 95% confidence interval = 1.01–1.45) in the SMCSGES genotyping cohort (&lt;i&gt;n&lt;/i&gt; = 5,072). In vitro luciferase assay showed the minor allele “A” of rs35594717 (tagged by rs9549246) was significantly associated with a higher &lt;i&gt;FOXO1&lt;/i&gt; promoter activity (&lt;i&gt;p&lt;/i&gt; &amp;lt; 0.05). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; &lt;i&gt;FOXO1&lt;/i&gt; 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 &lt;i&gt;FOXO1&lt;/i&gt; and contribute to the development of AR in the SMCSGES population. </jats:p>journal-article