Mateos Marion K, Tulstrup Morten, Quinn Michael Cj, Tuckuviene Ruta, Marshall Glenn M, Gupta Ramneek, Mayoh Chelsea, Wolthers Benjamin O, Barbaro Pasquale M, Ruud Ellen, Sutton Rosemary, Huttunen Pasi, Revesz Tamas, Trakymiene Sonata S, Barbaric Draga, Tedgård Ulf, Giles Jodie E, Alvaro Frank, Jonsson Olafur G, Mechinaud Françoise, Saks Kadri, Catchpoole Daniel, Kotecha Rishi S, Dalla-Pozza Luciano, Chenevix-Trench Georgia, Trahair Toby N, MacGregor Stuart, Schmiegelow Kjeld
Kids Cancer Centre, Sydney Children's Hospital Randwick, Sydney, NSW 2031, Australia.
School of Women and Children's Health, University of New South Wales (UNSW), Sydney, NSW 2052, Australia.
Cancers (Basel). 2020 May 19;12(5):1285. doi: 10.3390/cancers12051285.
Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied.
We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included.
No SNPs reached genome-wide significance ( < 5 × 10) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) ( < 1 × 10), two loci had concordant effects in both cohorts: (rs1804772) (MAF: 1%; = 3.95 × 10) that influences arachidonic acid metabolism and thus platelet aggregation, and (rs570684) (MAF: 1%; = 4.34 × 10) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease.
This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
有症状的静脉血栓栓塞症（VTE）发生在5%接受急性淋巴细胞白血病（ALL）治疗的儿童中，但不同ALL治疗方案中是否存在遗传易感性尚未得到充分研究。
我们对北欧/波罗的海2008年急性淋巴细胞白血病（ALL2008）队列和澳大利亚ALL治疗相关副作用风险评估（ERASE）队列中连续接受治疗的儿童进行了VTE的全基因组关联研究（GWAS）荟萃分析。共纳入92例病例和1481例欧洲血统对照。
在两个队列中，没有单核苷酸多态性（SNP）达到全基因组显著性水平（<5×10）。在排名前34的单核苷酸多态性（SNP）（<1×10）中，有两个位点在两个队列中具有一致的效应：（rs1804772）（MAF：1%；=3.95×10）影响花生四烯酸代谢，从而影响血小板聚集，以及（rs570684）（MAF：1%；=4.34×10），此前已与缺血性中风、动脉粥样硬化和早发性冠状动脉疾病的风险相关。
这是迄今为止针对接受儿童ALL方案治疗的儿童和青少年中SNP与VTE关联进行的最大规模GWAS荟萃分析。需要对这些发现进行验证，然后可能会导致对VTE预防干预措施进行患者分层。由于VTE止血涉及多个途径，需要更强大的GWAS来检测与VTE相关的变异组合。
