Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia.
Glucocorticoids are important therapy for acute lymphoblastic leukemia (ALL) and their major adverse effect is osteonecrosis. Our goal was to identify genetic and nongenetic risk factors for osteonecrosis. We performed a genome-wide association study of single nucleotide polymorphisms (SNPs) in a discovery cohort comprising 2285 children with ALL, treated on the Children's Oncology Group AALL0232 protocol (NCT00075725), adjusting for covariates. The minor allele at SNP rs10989692 (near the glutamate receptor GRIN3A locus) was associated with osteonecrosis (hazard ratio = 2.03; P = 3.59 × 10(-7)). The association was supported by 2 replication cohorts, including 361 children with ALL on St. Jude's Total XV protocol (NCT00137111) and 309 non-ALL patients from Vanderbilt University's BioVU repository treated with glucocorticoids (odds ratio [OR] = 1.87 and 2.26; P = .063 and .0074, respectively). In a meta-analysis, rs10989692 was also highest ranked (P = 2.68 × 10(-8)), and the glutamate pathway was the top ranked pathway (P = 9.8 × 10(-4)). Osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia (OR = 1.64; P = 2.5 × 10(-3)), and arterial embolism and thrombosis (OR = 1.88; P = 4.2 × 10(-3)). In conclusion, osteonecrosis was associated with inherited variations near glutamate receptor genes. Further understanding this association may allow interventions to decrease osteonecrosis. These trials are registered at www.clinicaltrials.gov as #NCT00075725 and #NCT00137111.
Department of Oncology and.
Seth E
SE
Karol
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
Wenjian
W
Yang
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN;
Sara L
SL
Van Driest
Department of Oncology and.
Tamara Y
TY
Chang
Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN; Department of Radiology, University of Tennessee, Memphis, TN;
Sue
S
Kaste
Office of Research.
Erica
E
Bowton
Office of Research.
Melissa
M
Basford
Department of Biomedical Informatics.
Lisa
L
Bastarache
Department of Pharmacology, and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;
Dan M
DM
Roden
Department of Biomedical Informatics, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;
Joshua C
JC
Denny
Department of Pediatrics, Maine Medical Center, Portland, ME;
Eric
E
Larsen
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX;
Naomi
N
Winick
Department of Pediatrics, New York University Langone Medical Center, New York, NY;
William L
WL
Carroll
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN;
Cheng
C
Cheng
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN;
Deqing
D
Pei
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
Christian A
CA
Fernandez
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
Chengcheng
C
Liu
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
Colton
C
Smith
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
Mignon L
ML
Loh
Department of Pediatrics, University of Utah, Salt Lake City, UT;
Elizabeth A
EA
Raetz
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA;
Stephen P
SP
Hunger
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX;
Paul
P
Scheet
Department of Oncology and.
Sima
S
Jeha
Department of Oncology and.
Ching-Hon
CH
Pui
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
William E
WE
Evans
Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL; and.
Meenakshi
M
Devidas
HARP Pharma Consulting, Mystic, CT.
Leonard A
LA
Mattano
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
Mary V
MV
Relling
D015415:Biomarkers / Q000378:metabolism*; D002648:Child; D015331:Cohort Studies; D003907:Dexamethasone / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D009367:Neoplasm Staging; D010020:Osteonecrosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012307:Risk Factors
D015415:Biomarkers; C548929:GRIN3A protein, human; D005938:Glucocorticoids; D016194:Receptors, N-Methyl-D-Aspartate; D003907:Dexamethasone