Potential Genetic Risk Factors for Chronic ITP of Childhood.

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Abstract While well recognized as an autoantibody mediated disease, the pathophysiology of childhood ITP remains poorly understood. Approximately 20% of children diagnosed with acute ITP will have persistent thrombocytopenia for more than 6 months after the original diagnosis. One hypothesis is that the autoantibody coated platelets are bound by surface Fcγ receptors in the reticuloendothelium system, which then target these platelets for destruction. Although the FcγRIIIA receptor usually shows weak binding, the phenylalanine (F) to valine (V) mutation in the FcγRIIIA receptor results in a higher affinity for IgG1 and IgG3. To test the possibility that the FcγRIIIA receptor genotype is associated with increased autoantibody mediated platelet destruction in ITP, we screened more than 80 ITP patients for this single nucleotide polymorphism (SNP) using an amplicon-down format for a custom Nanochip molecular biology workstation microarray assay. We observed a large shift in the allele frequencies of the FcγRIIIA receptor SNP (F158V) in ITP patients compared to controls (F =.36, V =.64 vs F =.70, V =.30; P<.001). When we analyzed the ITP patients with regard to chronicity of ITP, we found that chronic ITP patients showed a larger V allele frequency shift (F =.45, V =.55) than acute ITP patients (F =.58, V =.42). The IL-1α-889 SNP genotypes of these ITP patients were also found to have allele frequencies significantly different from controls (C =.67, T =.33 vs C =.84, T =.16, P =.005). FcγRIIIA SNP Genotype FF FV VV significance ITP patients 12.3 46.5 41 Controls 50.2 39.2 10.4 P<0.001 IL-1 α SNP Genotype CC CT TT significance ITP patients 51.4 33.3 15.2 Controls 71 26.3 2.6 P=0.005 Additionally, we have shown that the VV genotype of FcγRIIIA receptor is associated with 100% response to IVIg treatment in childhood ITP (Tarantino et al J. Thromb. Haemost. 2005). Thus, we propose that the FcγRIIIA receptor and IL-1α-889 genotypes may be useful as potential risk factors for ITP and its response to therapy. Understanding the mechanism whereby these polymorphisms alter the incidence and course of ITP in children will provide critical information in the prevention and treatment of this syndrome.

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