Genetic variants in toll‐like receptor 4 are associated with lack of steroid‐responsiveness in pediatric ITP patients

Abstract

Although the most common front‐line therapies for immune thrombocytopenia (ITP) have been in use for decades, it is still not possible to predict an individual patient's clinical course and response to therapy. Patients are managed with a trial‐and‐error approach and often suffer side effects of therapies which could have been avoided if response prediction were possible. Corticosteroids are the most frequently used upfront therapy for adults and children with ITP. Our group performed whole exome sequencing on a cohort of pediatric ITP patients, and identified two missense single nucleotide variants (SNV) in Toll‐like receptor 4 (TLR4). These coding variants in TLR4 had an increased frequency in Caucasian patients with poor response to upfront steroid therapy. Both TLR4 (D299G; rs4986790) and TLR4 (T399I; rs4986791) had a minor allele frequency (MAF) of 20.7% in those patients unresponsive to steroids, but were present at lower allele frequencies of 2.3% and 3.4% in responders respectively (P < .001). These findings were consistent with the trend identified in an independent cohort of pediatric ITP patients treated with corticosteroids who underwent direct genotyping for both SNVs. This study identified two candidate genetic variants in two unique cohorts of ITP patients which may contribute to steroid response and have prognostic implications for treatment response in ITP.

rs1800890 Polymorphism of IL-10 and Susceptibility to Idiopathic Thrombocytopenic Purpura

“…2,14 The most common complication is severe intracranial hemorrhage, with a bleeding mortality risk of 1% in children and 5% in adults. 2,15 ITP's actual etiology is unclear. However, this condition has various pathways, most of which are linked to immune system disorders.…”

Frequency of toll‐like receptor 4 variants and association with treatment response in children with primary immune thrombocytopenia

“…However, there are no available validated predictors for patient's clinical course and response to treatment. 2,7,8 Moreover, the exact etiology of ITP has not been completely understood, and could be attributed to an interaction between genetic and environmental factors. 3,9 A growing body of evidence indicates an important role of toll-like receptor 4 (TLR4) variants in autoimmune disorders.…”

“…10,11 Among the TLR4 variants, c.896A>G (p.Asp299Gly; rs4986790) and c.1196C>T (p.Thr399Ile; rs4986791), are located in a leucine-rich repeat of the extracellular TLR4 domain. 7,12 Both variants may be involved in pITP by contributing to increased inflammation and/or impeding the antiinflammatory effects of therapeutic agents (e.g., steroids). 7,13 However, only one study investigated the role of TLR4 p.Asp299Gly and p.Thr399Ile variants in children with ITP, which found an association with poor response to steroid therapy.…”

“…7,12 Both variants may be involved in pITP by contributing to increased inflammation and/or impeding the antiinflammatory effects of therapeutic agents (e.g., steroids). 7,13 However, only one study investigated the role of TLR4 p.Asp299Gly and p.Thr399Ile variants in children with ITP, which found an association with poor response to steroid therapy. 7 This could have important clinical implications, which calls for further research.…”

“…7,13 However, only one study investigated the role of TLR4 p.Asp299Gly and p.Thr399Ile variants in children with ITP, which found an association with poor response to steroid therapy. 7 This could have important clinical implications, which calls for further research.…”