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 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.
French
Deborah
D
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 338105-2794, USA.
Hamilton
Leo H
LH
Mattano
Leonard A
LA
Sather
Harland N
HN
Devidas
Meenakshi
M
Nachman
James B
JB
Relling
Mary V
MV
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D002648:Child; D004252:DNA Mutational Analysis; D003907:Dexamethasone / Q000009:adverse effects; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D010020:Osteonecrosis / Q000209:etiology / Q000235:genetics*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications*; D011237:Predictive Value of Tests
D017395:Plasminogen Activator Inhibitor 1; D003907:Dexamethasone