title: Association of polymorphisms in the TLR4 gene with the risk of developing neutropenia in children with leukemia.
abstract: Infections are a major cause of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). Susceptibility to infections increases as the neutrophil count decreases. Despite identical treatment patients vary considerably in the number of neutropenic episodes. Toll-like receptor 4 (TLR4) has been shown to have a role in inhibiting apoptosis of neutrophils. Therefore, we hypothesized that polymorphisms in the TLR4 gene may influence the number of chemotherapy-induced neutropenic episodes. Eight single-nucleotide polymorphisms (SNPs) of the TLR4 gene were determined in 194 children aged 0-17 years, who were diagnosed with ALL. We compared the genotype distributions of the SNPs with the frequency of neutropenic episodes during treatment with chemotherapeutic regimens. The number of neutropenic episodes varied from 0 to 17, with a median of four neutropenic episodes. Four SNPs in the TLR4 gene (rs10759931, rs11536889, rs1927911 and rs6478317) were associated with an increased risk of developing chemotherapy-induced neutropenia, each sustaining correction for multiple testing. Further studies are required to elucidate whether pediatric patients with ALL with the particular SNPs in the TLR4 gene also experience more infections and would benefit from prophylactic antibiotic treatment, by a reduction of morbidity and mortality due to infections.
authors.affiliation: Department of Pediatric Oncology and Pediatric Hematology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: K G E
authors.initials: KG
authors.lastname: Miedema
authors.forename: E M
authors.initials: EM
authors.lastname: te Poele
authors.forename: W J E
authors.initials: WJ
authors.lastname: Tissing
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
authors.forename: A P
authors.initials: AP
authors.lastname: de Pagter
authors.forename: W A
authors.initials: WA
authors.lastname: Kamps
authors.forename: B Z
authors.initials: BZ
authors.lastname: Alizadeh
authors.forename: H M
authors.initials: HM
authors.lastname: Boezen
authors.forename: E S J M
authors.initials: ES
authors.lastname: de Bont
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007223:Infant; D009503:Neutropenia / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4