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Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia.

Abstract
Cancer immunotherapy by immune checkpoint blockade has been effective in the treatment of certain tumors. However, the association between immune checkpoints and autoimmune diseases remains elusive and requires urgent investigation. Primary immune thrombocytopenia (ITP), characterized by reduced platelet count and a consequent increased risk of bleeding, is an autoimmune disorder with a hyper-activated T cell response. Here, we investigated the contribution of immune checkpoint-related single-nucleotide polymorphisms (SNPs), including CD28, ICOS, PD1, TNFSF4, DNAM1, TIM3, CTLA4, and LAG3 to the susceptibility and therapeutic effects of ITP. In this case-control study, 307 ITP patients and 295 age-matched healthy participants were recruited. We used the MassARRAY system for genotyping immune checkpoint-related SNPs. Our results revealed that rs1980422 in CD28 was associated with an increased risk of ITP after false discovery rate correction (codominant, CT vs. TT, OR = 1.788, 95% CI = 1.178-2.713, p = 0.006). In addition, CD28 expression at both the mRNA and protein levels was significantly higher in patients with CT than in those with the TT genotype (p = 0.028 and p = 0.001, respectively). Furthermore, the T allele of PD1 rs36084323 was a risk factor for ITP severity and the T allele of DNAM1 rs763361 for corticosteroid-resistance. In contrast, the T allele of LAG3 rs870849 was a protective factor for ITP severity, and the T allele of ICOS rs6726035 was protective against corticosteroid-resistance. The TT/CT genotypes of PD1 rs36084323 also showed an 8.889-fold increase in the risk of developing refractory ITP. This study indicates that immune checkpoint-related SNPs, especially CD28 rs1980422, may be genetic factors associated with the development and treatment of ITP patients. Our results shed new light on prognosis prediction, disease severity, and discovering new therapeutic targets.
AuthorsShuwen Wang, Xiaoyu Zhang, Shaoqiu Leng, Qirui Xu, Zi Sheng, Yanqi Zhang, Jie Yu, Qi Feng, Ming Hou, Jun Peng, Xiang Hu
JournalFrontiers in immunology (Front Immunol) Vol. 11 Pg. 615941 ( 2020) ISSN: 1664-3224 [Electronic] Switzerland
PMID33584705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 Wang, Zhang, Leng, Xu, Sheng, Zhang, Yu, Feng, Hou, Peng and Hu.
Chemical References
  • Adrenal Cortex Hormones
  • CD28 Antigens
  • Immune Checkpoint Proteins
Topics
  • Adrenal Cortex Hormones (pharmacology, therapeutic use)
  • Adult
  • Asian People (genetics)
  • CD28 Antigens (biosynthesis, genetics)
  • Case-Control Studies
  • Disease Progression
  • Drug Resistance (genetics)
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Immune Checkpoint Proteins (genetics)
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Polymorphism, Single Nucleotide
  • Purpura, Thrombocytopenic, Idiopathic (drug therapy, genetics, immunology)
  • Treatment Outcome

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