Sio Yang Yie, Du Kefan, Lam Terence Yin Weng, Say Yee-How, Reginald Kavita, Chew Fook Tim
Department of Biological Sciences, National University of Singapore, Singapore, Singapore,
Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
Int Arch Allergy Immunol. 2025;186(1):1-11. doi: 10.1159/000540686. Epub 2024 Aug 29.
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.
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.
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).
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.
FOXO1在调节导致过敏性炎症的免疫过程中发挥重要作用；然而，影响AR发病机制中FOXO1表达的基因变异仍不清楚。本研究旨在通过进行基因关联和功能分析研究，探讨FOXO1单核苷酸多态性（SNP）对AR发生发展的功能影响。
本研究属于正在进行的新加坡/马来西亚横断面遗传学和流行病学研究（SMCSGES）的一部分。我们在来自SMCSGES人群的n = 658名个体的亚队列中，评估外周血单核细胞（PBMC）中FOXO1转录本表达水平与AR表型、总鼻症状评分（TNSS）和SNP基因型之间的关联。在来自SMCSGES人群的n = 5,072名个体的队列中评估FOXO1 SNP与AR的关联。体外启动子荧光素酶测定用于评估AR相关SNP对FOXO1启动子活性的影响。
PBMC中FOXO1转录本表达与AR风险（p < 0.05）及AR患者的TNSS（p < 0.0001）显著相关。我们在来自SMCSGES亚队列和多民族eQTLGen联盟的PBMC中，鉴定出标签SNP rs9549246与FOXO1转录本表达之间存在显著关联（错误发现率调整后p < 0.05）。在SMCSGES基因分型队列（n = 5,072）中，标签SNP rs9549246的次要等位基因“A”与较高的AR风险显著相关（p = 0.04422，比值比 = 1.21，95%置信区间 = 1.01 - 1.45）。体外荧光素酶测定显示，rs35594717（由rs9549246标记）的次要等位基因“A”与较高的FOXO1启动子活性显著相关（p < 0.05）。
PBMC中FOXO1转录本表达与AR风险及症状严重程度密切相关。在SMCSGES人群中，由rs9549246标记的基因变异显示会影响FOXO1的表达并促成AR的发生发展。
