PS1489 TH1 CYTOKINE IFN‐GAMMA+874T/A AND TNF‐ALPHA‐857C/T POLYMORPHISMS AFFECT THROMBOCYTOPENIA IN CHRONIC IMMUNE THROMBOCYTOPENIA (CITP)
Authors: Souma K. , Saitoh T. , Murakami Y. , Ishihara R. , Awata M. , Gotoh N. , Kasamatsu T. , Handa H. , Murakami H. 
Published: June 2019

Background:

Chronic immune thrombocytopenia (cITP) is an acquired autoimmune disorder characterized by the production of anti‐platelet antibodies, resulting in the destruction of platelets and inhibition of their production. Th1 polarization is involved in the pathogenesis and disease status of cITP. Many investigators have reported IFN‐γ was upregulated at both the mRNA and protein levels in cITP patients. Several investigators have also reported that the Th1/Th2 ratio is inversely correlated with disease severity. These findings demonstrate that Th1 polarization is consistent with characteristics of cITP. However, it remains unclear that whether genetic factors of Th1 cytokines/chemokines affect the clinical features of cITP.

Aims:

We investigated the impact of Th1 cytokines/chemokine polymorphisms, including IL‐2, TNF‐α, CXCL10, IL‐18, IFN‐γ, and IFN‐γR on the severity of cITP.

Methods:

We examined 114 Japanese cITP patients (85 females and 29 males with a median age of 63.2 [range: 17.4–86.7] years). cITP was defined as isolated thrombocytopenia (platelet count <100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia according to the criteria of the ITP International Working Group. “Severe thrombocytopenia” was defined as a platelet count <20 × 109/L. Genotyping of IL‐2–330T/G, TNF‐α‐857C/T, CXCL10–1447A/G, IL‐18–607C/A IL‐18–137G/C, IFN‐γ+874T/A, IFN‐γR‐611G/A polymorphisms were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. “Severe thrombocytopenia” and bleeding tendency were compared using the χ2‐test. Multivariate analysis for “severe thrombocytopenia” and bleeding tendency performed using the logistic regression model. P < 0.05 was considered to represent statistical significance. All patients were provided written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital.

Results:

The platelet count ranged from 1 × 109/L to 96 × 109[t1] /L with a median of platelet count of 21 × 109/L at the initial diagnosis. In addition, 70 patients (61.4%) had bleeding tendency. Steroid treatment was given to 74 patients (64.9%), and eradication of Helicobacter pylori (H. pylori) was performed in 40 patients (35.4%), while splenectomy was performed in only 18 patients (15.8%). cITP patients with IFN‐γ+874 non‐AA genotype (high expression type) showed a significantly higher frequency of severe thrombocytopenia at diagnosis than AA genotype (low expression type) (73.3% vs 42.4% respectively, odds ratio [OR] = 3.73, 95% confidence interval [CI] = 1.11–12.54, p = 0.025). ITP patients with IL‐18–607 nonCC genotype showed a significantly higher frequency of bleeding tendency than CC genotype (65.3% vs 60.0% respectively, OR = 3.14, 95% CI = 1.05–9.37, p = 0.034). Multivariate analysis showed that the IFN‐γ+874 nonAA genotype was an independent predictor of “severe thrombocytopenia” at diagnosis (HR = 4.781, 95% CI = 1.27–18.0, p = 0.02). Furthermore, “severe thrombocytopenia” during observed period showed that the TNF‐α‐857 nonCC genotype (high producer type) was an independent significantly affecting factor (HR = 3.067, 95%CI = 1.17–8.03, p = 0.02).

Summary/Conclusion:

Our study revealed that IFN‐γ+874T/A and TNF‐α‐857C/T is associated with thrombocytopenia in cITP. These findings indicate that Th1 cytokine polymorphisms affect the severity of cITP.