Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.
Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.
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DOI：
10.1002/cpt.463
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发表时间：
2017-03
影响因子：
6.7
通讯作者：
Relling MV
中科院分区：
文献类型：
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作者：
Liu C;Yang W;Pei D;Cheng C;Smith C;Landier W;Hageman L;Chen Y;Yang JJ;Crews KR;Kornegay N;Karol SE;Wong FL;Jeha S;Sandlund JT;Ribeiro RC;Rubnitz JE;Metzger ML;Pui CH;Evans WE;Bhatia S;Relling MV
我们对1026例白血病患儿的原发性红细胞TPMT活性进行了全基因组关联研究。调整年龄和血统后，TPMT是唯一达到全基因组显著性的基因（最高命中rs1142345或719A>G，P = 8.6 × 10−61）。其他遗传变异（除了3个SNP rs1800462、rs1800460和rs1142345定义的TPMT临床基因型）没有显著提高TPMT表型的分类准确性。839例患者的临床巯基嘌呤耐受性与TPMT临床基因型相关（P = 2.4 × 10−11）。使用177个淋巴母细胞样细胞系（LCL），有251个SNP的排名高于最高的TPMT SNP（rs1142345 P = 6.8 × 10−5），显示了LCL在药物基因组学发现方面的局限性。在GWAS中，患者的TPMT活性表现为单基因性状，进一步支持了TPMT基因检测在临床中的实用性。
We performed a genome-wide association study of primary erythrocyte TPMT activity in children with leukemia (n = 1026). Adjusting for age and ancestry, TPMT was the only gene that reached genome-wide significance (top hit rs1142345 or 719A>G, P = 8.6 × 10−61). Additional genetic variants (besides the 3 SNPs rs1800462, rs1800460 and rs1142345 defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10−11). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345 P = 6.8 × 10−5), showing the limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic.