多药耐药基因多态性与儿童急性淋巴细胞性白血病相关性的研究

摘要

目的 探讨中国汉族儿童多药耐药基因( MDR1)3个位点的单核苷酸多态(12外显子1236 C→T突变、21外显子2677 G→T/A突变、26外显子3435C→T突变)与儿童急性淋巴细胞性白血病(ALL)的相关性.方法 通过多重单碱基延伸反应(SNaPshot SNP分型技术)检测176例ALL患儿和170例对照组儿童的MDR1 C1236T、G2677T/A、C3435T基因型分布.统计各位点基因型频率以及C1236T-G2677T/A-C3435T单倍体型频率.结合临床分型,比较不同基因型、单倍体型与儿童ALL发病风险、临床危险度的相关性.结果 MDR1 C3435T位点的基因型分布频率在病例组与对照组中存在差异.病例组中,MDR1 3435位点的T等位基因频率(55.1％)明显高于对照组中T等位基因频率(35％),差异有统计学意义(P =0.000).MDR1 3435位点的基因型TT与儿童ALL发病相关(P=0.000,OR=4.504).MDR1的3个位点间1236、2677、3435存在连锁不平衡性,共检出10种单倍体型( C1236T-G2677T/A-C3435T),其中以TTT( 32.30％)、TGC( 25.84％)、CGC( 16.85％)及CAC(16.29％)四种单倍体型为主.单倍体型CGT在病例组(0.30％)和对照组(1.97％)间分布差异有统计学意义(P =0.034).单倍体型TTT/TTT在高危组分布频率较高(16.6％)(P=0.037).结论 MDR1 C3435T的基因多态性与儿童ALL易感性相关.MDR1的C1236T-G2677T/A-C3435T单倍体型可以考虑作为评判ALL危险度的指标之一.%Objective To investigate the relationship between genetic polymorphism in exon 12 C1236T,exon 21 G2677T/A and exon 26 C3435T of the multidrug resistance 1 ( MDRI ) gene and the risk of childhood acute lymphocytic leukemia (ALL).Method A total of 176 patients with ALL and a cohort of 170 matched healthy subjects were included. SNaPshot SNP typing was used to determine the genotypes of MDR1 C1236T,G2677T/A,C3435T. Based on the clinical data, the relationship between genetic polymorphism of MDR1 and the risk of childhood ALL was analyzed. Result There was significant difference in the distribution of genotype of MDR1 C3435T between the group of controls and cases. The mutant homozygous TT genotype was found to be associated with occurrence of ALL ( P =0.000 ; OR =4.504). The data show evidence of pairwise linkage disequilibrium between the three common SNPs (C1236T-G2677T/A-C3435T). The haplotypes of TTT,TGC,CGC and CAC were predominant. The haplotype CGT distributed significantly differently between the groups of controls and cases ( P =0.034).The frequency of the haplotype TTT/TTT in the high risk group was higher than the other groups ( P =0.037).Conclusion The present findings suggest that 3435C→T polymorphism in MDR1 gene may be a genetic susceptibility factor for ALL.The haplotype of MDR1 (C1236T-G2677T/ A-C3435T) could be the clinical parameter at diagnosis.