A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group

As glucocorticoid use increased in acute lymphoblastic leukemia, osteonecrosis became an increasingly frequent complication. Besides increased age, host risk factors are poorly defined. We tested whether 12 polymorphisms were associated with osteonecrosis among patients 10 years and older treated on...

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Bibliographic Details
Published in:Blood 2008-05, Vol.111 (9), p.4496-4499
Main Authors: French, Deborah, Hamilton, Leo H., Mattano, Leonard A., Sather, Harland N., Devidas, Meenakshi, Nachman, James B., Relling, Mary V.
Format: Article
Language:English
Subjects:
Adolescent
Adult
Analysis of Variance
Child
Clinical Trials and Observations
Dexamethasone - adverse effects
DNA Mutational Analysis
Female
Genetic Predisposition to Disease
Genotype
Humans
Male
Osteonecrosis - etiology
Osteonecrosis - genetics
Plasminogen Activator Inhibitor 1 - genetics
Polymorphism, Genetic
Precursor Cell Lymphoblastic Leukemia-Lymphoma - complications
Predictive Value of Tests
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Summary:As glucocorticoid use increased in acute lymphoblastic leukemia, osteonecrosis became an increasingly frequent complication. Besides increased age, host risk factors are poorly defined. We tested whether 12 polymorphisms were associated with osteonecrosis among patients 10 years and older treated on the CCG1882 protocol. Candidate genes (TYMS, MTHFR, ABCB1, BGLAP, ACP5, LRP5, ESR1, PAI-1, VDR, PTH, and PTHR) were chosen based on putative mechanisms underlying osteonecrosis risk. All children received dexamethasone, with doses varying by treatment arm. A PAI-1 polymorphism (rs6092) was associated with risk of osteonecrosis in univariate (P = .002; odds ratio = 2.79) and multivariate (P = .002; odds ratio = 2.89) analyses (adjusting for gender, age, and treatment arm). Overall, 21 of 78 (26.9%) children with PAI-1 GA/AA genotypes, versus 25 of 214 (11.7%) children with GG genotype, developed osteonecrosis. PAI-1 polymorphisms and PAI-1 serum levels have previously been associated with thrombosis. We conclude that PAI-1 genetic variation may contribute to risk of osteonecrosis.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-11-123885