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Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children

Mateos, Marion K. ; Tulstrup, Morten ; Quinn, Michael C.J. ; Tuckuviene, Ruta ; Marshall, Glenn M. ; Gupta, Ramneek ; Mayoh, Chelsea ; Wolthers, Benjamin O. ; Barbaro, Pasquale M. and Ruud, Ellen , et al. (2020) In Cancers 12(5).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Acute lymphoblastic leukemia, Child, Genome-wide association study, Single-nucleotide polymorphism, Venous thromboembolism
in
Cancers
volume
12
issue
5
article number
1285
publisher
Multidisciplinary Digital Publishing Institute (MDPI)
external identifiers
  • pmid:32438682
  • scopus:85085388410
ISSN
2072-6694
DOI
10.3390/cancers12051285
language
English
LU publication?
yes
id
e7e66dab-6fe1-4328-b9c6-77a3182c8ffd
date added to LUP
2020-06-24 09:39:33
date last changed
2021-02-23 02:34:08
@article{e7e66dab-6fe1-4328-b9c6-77a3182c8ffd,
  abstract     = {<p>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 &lt; 5 × 10<sup>−8</sup>) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p &lt; 1 × 10<sup>−6</sup>), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10<sup>−7</sup>) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10<sup>−7</sup>) 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.</p>},
  author       = {Mateos, Marion K. and Tulstrup, Morten and Quinn, Michael C.J. and Tuckuviene, Ruta and Marshall, Glenn M. and Gupta, Ramneek and Mayoh, Chelsea and Wolthers, Benjamin O. and Barbaro, Pasquale M. and Ruud, Ellen and Sutton, Rosemary and Huttunen, Pasi and Revesz, Tamas and Trakymiene, Sonata S. and Barbaric, Draga and Tedgård, Ulf and Giles, Jodie E. and Alvaro, Frank and Jonsson, Olafur G. and Mechinaud, Françoise and Saks, Kadri and Catchpoole, Daniel and Kotecha, Rishi S. and Dalla-Pozza, Luciano and Chenevix-Trench, Georgia and Trahair, Toby N. and Macgregor, Stuart and Schmiegelow, Kjeld},
  issn         = {2072-6694},
  language     = {eng},
  month        = {05},
  number       = {5},
  publisher    = {Multidisciplinary Digital Publishing Institute (MDPI)},
  series       = {Cancers},
  title        = {Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children},
  url          = {http://dx.doi.org/10.3390/cancers12051285},
  doi          = {10.3390/cancers12051285},
  volume       = {12},
  year         = {2020},
}