Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy.
Genome-Wide Study Links PNPLA3 Variant With Elevated Hepatic Transaminase After Acute Lymphoblastic Leukemia Therapy.
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DOI：
10.1002/cpt.629
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发表时间：
2017-07
影响因子：
6.7
通讯作者：
Relling MV
中科院分区：
文献类型：
--
作者：
Liu Y;Fernandez CA;Smith C;Yang W;Cheng C;Panetta JC;Kornegay N;Liu C;Ramsey LB;Karol SE;Janke LJ;Larsen EC;Winick N;Carroll WL;Loh ML;Raetz EA;Hunger SP;Devidas M;Yang JJ;Mullighan CG;Zhang J;Evans WE;Jeha S;Pui CH;Relling MV
急性淋巴细胞白血病（ALL）的缓解诱导治疗包括可能引起肝毒性的药物，包括天冬酰胺酶。我们使用全基因组关联研究（GWAS）来确定在St. Jude儿童研究医院（SJCRH）方案注册的ALL儿童诱导治疗后与谷丙转氨酶（ALT）水平升高相关的位点。利用阵列和外显子组测序对种系DNA进行基因分型。调整年龄、体重指数、血统、天冬酰胺酶制剂和剂量后，先前与脂肪肝风险相关的PNPLA3 rs738409 (C b> G) I148M变异与ALT的遗传相关性最强（P = 2.5×10−8）。PNPLA3 rs738409变异解释了3.8%的ALT变异性，并部分解释了ALT的种族相关差异。PNPLA3 rs738409关联在2,285名接受儿童肿瘤组方案AALL0232治疗的独立队列中得到了重复（P = 0.024）。这是一个药物遗传变异与疾病风险变异重叠的例子。
Remission induction therapy for acute lymphoblastic leukemia (ALL) includes medications that may cause hepatotoxicity, including asparaginase. We used a genome-wide association study (GWAS) to identify loci associated with elevated alanine transaminase (ALT) levels after induction therapy in children with ALL enrolled on St. Jude Children’s Research Hospital (SJCRH) protocols. Germline DNA was genotyped using arrays and exome sequencing. Adjusting for age, body mass index, ancestry, asparaginase preparation and dosage, the PNPLA3 rs738409 (C>G) I148M variant, previously associated with fatty liver disease risk, had the strongest genetic association with ALT (P = 2.5×10−8). The PNPLA3 rs738409 variant explained 3.8% of the variability in ALT, and partly explained race-related differences in ALT. The PNPLA3 rs738409 association was replicated in an independent cohort of 2,285 patients treated on Children’s Oncology Group protocol AALL0232 (P = 0.024). This is an example of a pharmacogenetic variant overlapping with a disease risk variant.
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影响因子：
3.7
作者：
Comuzzie AG;Cole SA;Laston SL;Voruganti VS;Haack K;Gibbs RA;Butte NF
通讯作者：
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影响因子：
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