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.