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

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.

© 2015 by The American Society of Hematology.

Figures

Figure 1

Cumulative incidence of osteonecrosis by rs10989692 genotype in COG AALL0232. The cumulative incidence of osteonecrosis was higher in those carrying the A allele at rs10989692 (5′ of GRIN3A) in COG AALL0232 (A) in all ancestry groups combined, adjusting for ancestry (n = 2285), and (B) among whites only (n = 1268).

Figure 2

Effect size for rs10989692 and rs2154490 genotypes by cohort. Effect sizes are computed as the HR for COG AALL0232 based on time-dependent analysis, and OR for SJ Total XV and Vanderbilt BioVU based on time-independent analyses. Effect sizes for rs10989692 and rs2154490 are shown after adjusting for age, gender, treatment arm, and ancestry in COG and SJ, and after adjusting for age, gender, and ancestry in Vanderbilt BioVU. Asterisk (*) denotes effect size.

Figure 3

Manhattan plot of results from meta-analysis. Inverse of log P value for SNP associations with osteonecrosis risk from meta-analysis of COG AALL0232 (n = 2285), SJ Total XV (n = 361), and Vanderbilt BioVU (n = 309), adjusting for age, gender, treatment, and ancestry group in COG AALL0232 and SJ, and adjusting for age, gender, and ancestry groups in Vanderbilt BioVU. SNPs near GRIN3A and within GRIK1 had the strongest association.