DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Glucocorticoid-induced osteonecrosis (age 10 years and older). The EFO term response to glucocorticoid, osteonecrosis was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: response to glucocorticoid, osteonecrosis

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

SE Karol, W Yang, SL Van Driest, TY Chang, S Kaste, E Bowton, M Basford, L Bastarache, DM Roden, JC Denny, E Larsen, N Winick, WL Carroll, C Cheng, D Pei, CA Fernandez, C Liu, C Smith, ML Loh, EA Raetz, SP Hunger, P Scheet, S Jeha, CH Pui, WE Evans, M Devidas, LA Mattano, MV Relling

TITLE:

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

JOURNAL:

Blood Oct 2015, Vol 126, pp. 1770-6

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. PUBMED: 26265699
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