Inflammation-Related Gene Polymorphisms Associated with Susceptibility to Primary Immune Thrombocytopenia

INTRODUCTION

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by a reduced platelet count and an increased risk of bleeding. Although immense research has improved our understanding of ITP and led to impressive therapeutics, the pathogenesis is still not completely clear and a large subset of patients are refractory to first- and second-line therapies.In this study, we investigated the involvement of a cluster of inflammation-related genes, including CD24, FCRL3, CD226, IL2, IRF5, ITGAM, NLRP3, CARD8, PTPN22, SH2B3, STAT4, TNFAIP3, and TRAF1 genes.

METHODS

In this case-control study, 261 ITP inpatients (92 males and 169 females) with a mean age of 39.59 ± 17.52 years were recruited from Qilu Hospital, Shandong University between January 2007 to April 2016. In addition, 154 healthy participants (60 males and 94 females) with a mean age of 44.82 ± 13.63 years were enrolled as a control group. Inflammation-related single nucleotide polymorphism (SNP) genotyping was performed on the Sequenom MassARRAY iPLEX platform. SNPs included CD24 rs8734/rs52812045, FCRL3 rs11264799, rs7528684, rs945635, rs3761959, CD226 rs763361, IL2 rs6822844, IRF5 rs2004640, rs2280714, rs10954213, ITGAM rs1143679, NLRP3 rs35829419, rs4353135, rs10754558, CARD8 rs2043211, PTPN22 rs33996649, rs1310182, SH2B3 rs3184504, STAT4 rs7574865, rs10181656, TNFAIP3 rs6920220, rs10499194, rs2230926, rs5029939, TRAF1 rs10818488. SPSS (Ver 22.0, Chicago, IL) was used to perform statistical analysis. The results of genotyping were analyzed with t or ¦Ö² tests. A Fisher's exact test was performed when expected frequencies were less than 5. Univariate and multivariate analyses were then performed by non-conditional logistic regression adjusting for age and gender. P values < 0.05 were considered significant. The two-tailed significance level was set at 0.05.

RESULTS

Genotype frequencies of these inflammation-related SNPs in healthy controls were consistent with the Hardy-Weinberg equilibrium (p > 0.05). Genotype distributions in ITP patients and controls are detailed in Table 1. Statistical analysis revealed a significant difference in TNFAIP3 rs10499194 and CD24 rs52812045 between patients and controls (Table 1). Genotype frequencies of other SNPs were not significantly different (p > 0.05). However, when allelic frequencies were compared, significant differences were not found in any genotyped SNPs (p > 0.05).

ITP is classified by duration into newly diagnosed (less than 3-month duration), persistent (3- to 12-month duration) and chronic (1-year duration). According to ordinal logistic regression, the genotype frequency of IRF5 rs2004640 was significantly different between the 3 ITP phases. Compared with heterozygous carriers, homozygous carriers of major allele were found in higher frequency in newly diagnosed patients. The OR for GG vs. GT was 0.472 (95%CI = 0.289-0.770, p = 0.003).

Patients with clinically relevant bleeding who require mandated treatment or additional therapeutic intervention are defined as having severe ITP. The inflammation-related SNPs were not significantly different between severe and non-severe patients (p > 0.05).

Interestingly, genotype frequency distribution of CARD8 rs2043211 was significantly higher in refractory patients than in non-refractory patients (OR = 4.191, 95%CI = 1.026-14.567, p = 0.040), while allelic frequencies were not significantly different. We also compared corticosteroid-sensitive and corticosteroid-resistant ITP patients. We found that the genotype frequency of NLRP3 rs4353135 was significantly different between the two groups, and heterozygous genotype was more frequent in corticosteroid-sensitive patients (OR = 0.413, 95%CI = 0.203-0.841, p = 0.015). No significant difference was observed in other polymorphisms.

CONCLUSIONS

Our study identifies SNPs that differ based on the presence of ITP (TNFAIP3 rs10499194 and CD24 rs52812045), the phase of ITP (IRF5 rs2004640), refractoriness (CARD8 rs2043211), and corticosteroid sensitivity (NLRP3 rs4353135) in Chinese Han population. These important findings may lead to more tailored treatment strategies for ITP patients. Further study will dissect how these SNPs exert their roles to affect the pathogenesis of ITP.

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