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Blood. 2015 Oct 8;126(15):1770-6. doi: 10.1182/blood-2015-05-643601. Epub 2015 Aug 11.

Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia.

Author information

1
Department of Oncology and.
2
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN;
3
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN;
4
Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, TN; Department of Radiology, University of Tennessee, Memphis, TN;
5
Office of Research.
6
Department of Biomedical Informatics.
7
Department of Pharmacology, and Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;
8
Department of Biomedical Informatics, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;
9
Department of Pediatrics, Maine Medical Center, Portland, ME;
10
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX;
11
Department of Pediatrics, New York University Langone Medical Center, New York, NY;
12
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN;
13
Department of Pediatrics, University of California School of Medicine, San Francisco, CA;
14
Department of Pediatrics, University of Utah, Salt Lake City, UT;
15
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA;
16
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX;
17
Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL; and.
18
HARP Pharma Consulting, Mystic, CT.

Abstract

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.

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PMID:
26265699
PMCID:
PMC4600016
DOI:
10.1182/blood-2015-05-643601
[Indexed for MEDLINE]
Free PMC Article

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