SHMT1多态性与ALL儿童HD-MTX不良反应的关系

  目的  研究丝氨酸羟甲基转移酶1(serine hydroxymethyltransferase 1, SHMT1)基因多态性与急性淋巴细胞白血病(acute lymphocytic leukemia, ALL)儿童大剂量甲氨蝶呤(high-dose methotrexate, HD-MTX)不良反应的相关性。  方法  本研究以51例接受HD-MTX化疗的ALL患儿为研究对象, 统计分析其应用HD-MTX后产生的临床表现; 提取mRNA后逆转录为cDNA, 利用变性梯度凝胶电泳(denaturing gradient gel electrophoresis, DGGE)结合DNA测序检测SHMT1多态性(rs1979277、rs3783、rs1979276、rs12952556), 并分析其与HD-MTX不良反应的关系。  结果  接受HD-MTX化疗的ALL患儿产生的严重不良反应主要表现为中性粒细胞减少和肝功能损害。rs3783(C>G)、rs1979276(C>T)、rs12952556(A>G)及rs1979277(C>T)的基因型分布情况相同, rs1979277多态性与中性粒细胞减少的发生风险无关(P>0.05), 但其CT及TT基因型可以降低肝功能损害的发生风险(CT: OR=0.129, 95% CI:0.020~0.817, P=0.03;TT:OR=0.103, 95% CI:0.017~0.620, P=0.013)。  结论  rs1979277、rs3783、rs1979276及rs12952556的联合作用与中性粒细胞减少的发生无关, 但它们之中一个或多个位点可能降低肝功能损害的发生。 

Correlations between the polymorphisms of serine hydroxymethyltransferase 1 gene and the adverse reactions of high-dose methotrexate in children with acute lymphoblastic leukemia

  Objective  To investigate the correlation between polymorphisms of serine hydroxymethyltransferase1 gene and the adverse reactions of high-dose methotrexate (HD-MTX) in children with acute lymphoblastic leukemia (ALL).  Methods  A total of 51 patients with ALL were treated with HD-MTX, and clinical manifestations after HD-MTX treatment were evaluated retrospectively.cDNA was obtained from mRNA.The polymorphisms of SHMT1 gene containing rs1979277, rs3783, rs1979276, and rs12952556 sites were tested by denaturing gradient gel electrophoresis and direct sequencing.Effects of SHMT1 gene polymorphisms on HD-MTX adverse reactions were evaluated.  Results  Severe adverse reactions in ALL patients treated with HD-MTX appeared to be mainly neutropenia and hepatoadverse reactions.The frequency distributions of rs3783(C>G), rs1979276(C>T), rs12952556(A>G), and rs1979277 (C>T) were the same.The polymorphisms of rs1979277 showed no correlation with neutropenia (P>0.05) but rs1979277 CT and TT genotypes were correlated with hepatoadverse reactions (CT:OR=0.129, 95% CI:0.020 to 0.817, P=0.03;TT:OR=0.103, 95% CI: 0.017 to 0.620, P=0.013).  Conclusion  No correlation was found between the combination of rs1979277, rs3783, rs1979276, rs12952556, and neutropenia, but one or more of these loci may reduce the risk of hepatoadverse reactions.