6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT1513 and NUDT1512 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT1513 and NUDT1512, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients. 相似文献
Glucocorticoids play essential roles in the treatment of childhood acute lymphoblastic leukaemia (ALL); however, treatment with these agents can result in severe side-effects. This study, the first of its kind in a Saudi population, investigates associations of ABCB1 gene polymorphisms (pharmacodynamics and pharmacokinetic) with the development of toxicity and side effects (glucose abnormality, liver toxicity and infection) in a small population of Saudi children with ALL.
Methods
Three single nucleotide polymorphisms (SNPs) of the ABCB1 gene (rs 3213619 T129C, rs 2032582 G2677T and rs1045642 C3435T) were analysed in 70 Saudi children with ALL and 60 control subjects. Participants were treated according to the ALL 2000 study protocol. Toxicities were assessed and associations with genotypes were evaluated according to Common Toxicity Criteria (NCI-CTC).
Results
Significant associations were observed among carriers and the mutated genotype C3435T (ABCB1), which had an incidence of infection (p?=?0.05). Although no correlations were found between liver toxicity and glucose abnormalities for patients carrying ABCB1 SNPs, risk factors for liver toxicity were elevated by a factor of three for patients carrying the SNP G2677T, OR 3.00 (1.034–8.702). The risk factor of glucose abnormality toxicity for the patients carring T129C were increased three times OR 3.06 (0.486–19.198).
Conclusions
In terms of infection incidence, polymorphism C3435T may contribute to potential life-threatening infections during paediatric ALL therapy, through glucocorticoid usage. 相似文献
Objectives: Optic neuritis (ON) is defined as inflammation of the optic nerve, which is mostly idiopathic. However, it can be associated with various causes (demyelinating lesions, autoimmune disorders, infectious and inflammatory conditions). Inflammatory demyelinating disorder of the optic nerve can be associated with multiple sclerosis. It is thought that CETP, SIRT1, FGFR2, STAT3, VEGFA and IL6 genes play a key role in this autoimmune inflammatory disease. The aim of our study was to determine if the frequency of the CETP, SIRT1, FGFR2, STAT3, VEGFA and IL6 gene polymorphisms have an influence on the development of acute ON.
Methods: The study enrolled patients with ON and a random sample of healthy population. The genotyping test of the CETPrs5882,rs708272, SIRT1rs12778366, FGFR2rs2981582, STAT3rs744166, VEGFArs833068, IL6rs1800795 polymorphisms was carried out using the RT-PCR method.
Results: Our study determined that the G/A genotype of CETPrs708272 was associated with two-fold-decreased odds of ON development under the codominant (OR = 0.495;95%CI:0.256–0.959) and overdominant (OR = 0.501;95%CI:0.280–0.895) models. Also, each allele C at VEGFArs833068 was associated with 1.7-fold increased odds of ON development under the additive model (OR = 1.733;95%CI:1.148–2.615). Furthermore, IL6 rs1800795 G/G genotype was associated with increased odds of ON development under the codominant (OR = 2.869;95%CI:1.280–6.434) and recessive (OR = 2.315;95%CI:1.251–4.285) models.
Conclusions: We revealed that the genotypes of CETPrs708272 G/A, IL6rs1800795 G/G, and each allele C at VEGFArs833068 were associated with ON. CETPrs708272 G/G genotype was associated with decreased by 62% odds of ON with MS development under the recessive (OR = 0.379;95%CI:0.155–0.929; p = .034) model. 相似文献
Backgrounds: Toll-like receptors 2; 4 (TLR2;4) are an essential component of the innate immunity and play an important role in immune-surveillance and immune response to various microorganisms. This study aimed to investigate the association between TLR2 and TLR4 polymorphism and the risk of acquiring severe infections, and impact on AML patient’s outcome. Subjects and methods: Using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP); we analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) in 120 AML patients and 100 healthy control subjects. Results: No significant differences in genotype or alleles frequency between healthy controls and AML patients regarding TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms (P>0.05 for all). Neutropenic fever was detected in 110 out of 120 (91.7%) of the studied AML patients. The sepsis and pneumonia were identified in 20 out of 120 patients (16.7%). The incidence of sepsis was associated with TLR2 Arg753Gln: AG genotypes, A allele and TLR4 Asp299Gly: CT genotype and C allele as compared to other genotypes and alleles. Moreover; TLR2 (Arg753Gln) GG polymorphisms significantly associated with shortest overall survival (OS) and shortest disease-free survival (DFS); while TLR4 polymorphisms affect the DSF only but not OS. In AML patients TLR2 Arg753Gln gene polymorphism is associated with high susceptibility to sepsis and TLR4 (Asp299Gly and Thr399Ile) gene polymorphism is associated with high susceptibility for both pneumonia; and sepsis. Conclusion: TLR2 Arg753Gln (AG; GG genotype) polymorphisms are associated with shortest OS and DFS. Moreover; significant association between TLR2 polymorphisms, TLR4 Arg753Gln polymorphisms and risk of severe infections in AML patients was documented. 相似文献