A genetic factor associated with low final bone mineral density in children after a long-term glucocorticoids treatment

• Published in: The pharmacogenomics journal 2017-03, Vol.17 (2), p.180-185
• Main Authors: Park, H-W, Tse, S, Yang, W, Kelly, H W, Kaste, S C, Pui, C-H, Relling, M V, Tantisira, K G
• Format: Article
• Language: English
• Subjects: 45/43; 631/208/2489; 692/499; Absorptiometry, Photon; Acute lymphoblastic leukemia; Age Factors; Anti-Asthmatic Agents - administration & dosage; Anti-Asthmatic Agents - adverse effects; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Asthma; Asthma - drug therapy; Biomedical and Life Sciences; Biomedicine; Bone density; Bone Density - drug effects; Bone Density - genetics; Bone mineral density; Child; Children; Drug Administration Schedule; Female; Gene Expression; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotype; Glucocorticoids; Glucocorticoids - administration & dosage; Glucocorticoids - adverse effects; Human Genetics; Humans; Lymphatic leukemia; Male; Oncology; original-article; Pediatrics; Pharmacogenetics; Pharmacogenomic Variants; Pharmacotherapy; Phenotype; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Prednisone; Prednisone - administration & dosage; Prednisone - adverse effects; Psychopharmacology; Replication; Risk Factors; Single-nucleotide polymorphism; Time Factors; Tomography, Spiral Computed; Treatment Outcome; United States
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/tpj.2015.92

Treatment with glucocorticoids is associated with lower bone mineral density (BMD). We performed a genome-wide association study to analyze interactive effects between genotypes and cumulative dose of prednisone (PD) over 4.3 years of follow-up period on the final BMD Z -scores in 461 white children from the Childhood Asthma Management Program. No variants met the conventional criteria for genome-wide significance, and thus we looked for evidence of replication. The top 100-ranked single-nucleotide polymorphisms (SNPs) were then carried forward replication in 59 children with acute lymphoblastic leukemia (ALL) exposed to large fixed doses of PD as part of their chemotherapeutic regimen. Among them, rs6461639 (interaction P =1.88 × 10 −5 in the CAMP population) showed a significant association with the final BMD Z -scores in the ALL population ( P =0.016). The association of the ALL population was only present after correction for the anti-metabolite treatment arm (high vs low dose). We have identified a novel SNP, rs6461639, showing a significant effect on the final BMD Z -scores in two independent pediatric populations after long-term high-dose PD treatment.