TY - JOUR
T1 - Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children
AU - Mateos, Marion K
AU - Tulstrup, Morten
AU - Quinn, Michael Cj
AU - Tuckuviene, Ruta
AU - Marshall, Glenn M
AU - Gupta, Ramneek
AU - Mayoh, Chelsea
AU - Wolthers, Benjamin O
AU - Barbaro, Pasquale M
AU - Ruud, Ellen
AU - Sutton, Rosemary
AU - Huttunen, Pasi
AU - Revesz, Tamas
AU - Trakymiene, Sonata S
AU - Barbaric, Draga
AU - Tedgård, Ulf
AU - Giles, Jodie E
AU - Alvaro, Frank
AU - Jonsson, Olafur G
AU - Mechinaud, Françoise
AU - Saks, Kadri
AU - Catchpoole, Daniel
AU - Kotecha, Rishi S
AU - Dalla-Pozza, Luciano
AU - Chenevix-Trench, Georgia
AU - Trahair, Toby N
AU - MacGregor, Stuart
AU - Schmiegelow, Kjeld
PY - 2020/5/19
Y1 - 2020/5/19
N2 - 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 × 10-8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10-6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10-7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 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.
AB - 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 × 10-8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10-6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10-7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 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.
KW - Acute lymphoblastic leukemia
KW - Child
KW - Genome-wide association study
KW - Single-nucleotide polymorphism
KW - Venous thromboembolism
UR - http://www.scopus.com/inward/record.url?scp=85085388410&partnerID=8YFLogxK
U2 - 10.3390/cancers12051285
DO - 10.3390/cancers12051285
M3 - Journal article
C2 - 32438682
SN - 2072-6694
VL - 12
JO - Cancers
JF - Cancers
IS - 5
M1 - 1285
ER -