期刊
CANCERS
卷 12, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/cancers12051285
关键词
acute lymphoblastic leukemia; child; genome-wide association study; single-nucleotide polymorphism; venous thromboembolism
类别
资金
- Kids Cancer Alliance (a Translational Cancer Research Centre of Cancer Institute NSW)
- Cancer Institute NSW [ECF181430]
- Anthony Rothe Memorial Trust
- Royal Australasian College of Physicians-Kids Cancer Project Research Entry Scholarship
- Cancer Therapeutics CRC (CTx) PhD Clinician Researcher Top-Up Scholarship
- Cancer Council NSW
- NHMRC Australia
- Tour de Cure
- Danish Cancer Society
- Danish Childhood Cancer Foundation
- Swedish Childhood Cancer Foundation
- Nordic Cancer Union
- Otto Christensen Foundation
- University Hospital Rigshospitalet
- Novo Nordisk Foundation
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. Methods: 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. Results: No SNPs reached genome-wide significance (p < 5 x 10(-8)) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 x 10(-6)), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 x 10(-7)) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 x 10(-7)) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: 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.
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