FOXO1 Single-Nucleotide Polymorphisms Are Associated with Bleeding Severity and Sensitivity of Glucocorticoid Treatment of Pediatric Immune Thrombocytopenia

Xingjuan Xie; Hao Gu; Jingyao Ma; Lingling Fu; Jie Ma; Jialu Zhang; Runhui Wu; Zhenping Chen

doi:10.1089/dna.2023.0431

FOXO1 Single-Nucleotide Polymorphisms Are Associated with Bleeding Severity and Sensitivity of Glucocorticoid Treatment of Pediatric Immune Thrombocytopenia

DNA Cell Biol. 2024 Apr 29. doi: 10.1089/dna.2023.0431. Online ahead of print.

Authors

Xingjuan Xie¹, Hao Gu^{1

2}, Jingyao Ma³, Lingling Fu³, Jie Ma³, Jialu Zhang³, Runhui Wu³, Zhenping Chen¹

Affiliations

¹ Hematologic Disease Laboratory, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
² Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
³ Department of Hematology, Beijing Key Laboratory of Pediatric Hematology Oncology; Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

PMID: 38683649
DOI: 10.1089/dna.2023.0431

Abstract

Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Emerging evidence indicates that FOXO1 SNPs are related to the immune dysregulation of several autoimmune diseases suggesting that FOXO1 may be involved in inflammation and pathologic activities in patients with ITP. This study aimed to evaluate whether FOXO1 gene single-nucleotide polymorphisms (SNPs) are associated with susceptibility to ITP and clinical priorities of concern include bleeding severity and sensitivity of glucocorticoid treatment. This study recruited 327 newly diagnosed ITP and 220 healthy controls. Four SNPs (rs17446593, rs17446614, rs2721068, and rs2721068) of the FOXO1 gene were detected using the Sequenom MassArray system. Bleeding severity were classified into the mild and severe groups based on the bleeding scores. ITP patients were classified as sensitive and insensitive to glucocorticoid treatment according to the practice guideline for ITP (2019 version). The frequencies of the four SNPs did not show any significant differences between the ITP and healthy control groups. Patients with AA genotype at rs17446593 (p = 0.009) and GG genotype at rs17446614 (p = 0.009) suffered more severe bleeding than patients without them. Carriers of haplotype G_rs17446593A_rs17446614C_rs2721068T_rs2755213 were protective to severe bleeding (p = 0.002). The AA genotype at rs17446593 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment (p = 0.03). Haplotype G_rs17446593G_rs17446614T_rs2721068T_rs2755213 increases the risk of glucocorticoid resistance (p = 0.007). Although FOXO1 gene polymorphisms were not associated with susceptibility to ITP, the AA genotype at rs17446593 and GG genotype at rs17446614 were associated with bleeding severity. Haplotype GACT have a protective effect against severe bleeding. Patients with AA genotype at rs17446593 may tend to have good responds to glucocorticoid treatment. However, the FOXO1 gene haplotype GGTT increases the risk of glucocorticoid-resistant. Trial registration: ChiCTR1900022419.

Keywords: FOXO1; bleeding severity; glucocorticoid treatment; immune thrombocytopenia; pediatrics; single-nucleotide polymorphism.