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

Seth E. Karol, Wenjian Yang, Sara L. Van Driest, Tamara Y. Chang, Sue Kaste, Erica Bowton, Melissa Basford, Lisa Bastarache, Dan M. Roden, Joshua C. Denny, Eric Larsen, Naomi Winick, William L. Carroll, Cheng Cheng, Deqing Pei, Christian A. Fernandez, Chengcheng Liu, Colton Smith, Mignon L. Loh, Elizabeth A. RaetzStephen P. Hunger, Paul Scheet, Sima Jeha, Ching Hon Pui, William E. Evans, Meenakshi Devidas, Leonard A. Mattano, Mary V. Relling

Research output: Contribution to journalArticle

52 Scopus citations

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 5 2.03; P 5 3.59 3 1027). 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]51.87 and 2.26;P5.063 and .0074, respectively). In ameta-analysis, rs10989692 was also highest ranked (P 5 2.68 3 1028), and the glutamate pathway was the top ranked pathway (P 5 9.8 3 1024). Osteonecrosis-associated glutamate receptor variants were also associated with other vascular phenotypes including cerebral ischemia (OR 5 1.64; P 5 2.5 3 1023), and arterialembolismandthrombosis (OR51.88;P54.231023). In conclusion,osteonecrosiswas associatedwith inheritedvariations near glutamate receptor genes. Further understandingthis associationmay allow interventions to decrease osteonecrosis. These trials are registered at www.clinicaltrials.gov as #NCT00075725 and #NCT00137111.

Original languageEnglish (US)
Pages (from-to)1770-1776
Number of pages7
JournalBlood
Volume126
Issue number15
DOIs
StatePublished - 2015

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Medicine(all)
  • Hematology
  • Cell Biology

Cite this

Karol, S. E., Yang, W., Van Driest, S. L., Chang, T. Y., Kaste, S., Bowton, E., Basford, M., Bastarache, L., Roden, D. M., Denny, J. C., Larsen, E., Winick, N., Carroll, W. L., Cheng, C., Pei, D., Fernandez, C. A., Liu, C., Smith, C., Loh, M. L., ... Relling, M. V. (2015). Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood, 126(15), 1770-1776. https://doi.org/10.1182/blood-2015-05-643601