Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes.
Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes.
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DOI：
10.2217/pgs.13.226
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发表时间：
2014-03
期刊：
影响因子：
2.1
通讯作者：
Lennard L
中科院分区：
文献类型：
--
作者：
Matimba A;Li F;Livshits A;Cartwright CS;Scully S;Fridley BL;Jenkins G;Batzler A;Wang L;Weinshilboum R;Lennard L
我们研究了儿童急性淋巴细胞白血病中与巯嘌呤代谢和临床反应相关的候选基因。我们使用淋巴母细胞系对6-硫鸟嘌呤和6-巯基嘌呤的细胞毒性进行了全基因组SNP关联研究。然后，我们对589名白种人英国ALL 97患者的DNA中与淋巴母细胞系细胞毒性相关的最高SNPs以及“硫嘌呤途径”基因的tagSNPs（共686个SNPs）进行基因分型。通过癌细胞系中的SiRNA敲除进行功能验证研究。巯基嘌呤途径基因ABCC 4、ABCC 5、IMPDH 1、ITPA、SLC 28 A3和XDH中的SNP，以及位于ATP 6AP 2、FRMD 4 B、GNG 2、KCNMA 1和NME 1内或附近的SNP，与临床反应和巯基嘌呤代谢的测量相关。功能验证显示这些基因的细胞毒性发生了变化。对硫嘌呤的临床反应可能受已知硫嘌呤途径基因和硫嘌呤途径外其他新基因的变异调节。
We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia. We performed genome-wide SNP association studies of 6-thioguanine and 6-mercaptopurine cytotoxicity using lymphoblastoid cell lines. We then genotyped the top SNPs associated with lymphoblastoid cell line cytotoxicity, together with tagSNPs for genes in the ‘thiopurine pathway’ (686 total SNPs), in DNA from 589 Caucasian UK ALL97 patients. Functional validation studies were performed by siRNA knockdown in cancer cell lines. SNPs in the thiopurine pathway genes ABCC4, ABCC5, IMPDH1, ITPA, SLC28A3 and XDH, and SNPs located within or near ATP6AP2, FRMD4B, GNG2, KCNMA1 and NME1, were associated with clinical response and measures of thiopurine metabolism. Functional validation showed shifts in cytotoxicity for these genes. The clinical response to thiopurines may be regulated by variation in known thiopurine pathway genes and additional novel genes outside of the thiopurine pathway.