title: A genetic factor associated with low final bone mineral density in children after a long-term glucocorticoids treatment.
abstract: 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 × 10-5in 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.
authors: The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors: H-W
authors: HW
authors: Park
authors: The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Sainte-Justine University Hospital Center, Montréal, Québec, Canada.
authors: S
authors: S
authors: Tse
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: W
authors: W
authors: Yang
authors: Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors: H W
authors: HW
authors: Kelly
authors: Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: S C
authors: SC
authors: Kaste
authors: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: C-H
authors: CH
authors: Pui
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors: M V
authors: MV
authors: Relling
authors: The Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors: K G
authors: KG
authors: Tantisira
mesh_terms: D015502:Absorptiometry, Photon; D000367:Age Factors; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001249:Asthma / Q000188:drug therapy*; D015519:Bone Density / Q000187:drug effects* / Q000235:genetics*; D002648:Child; D004334:Drug Administration Schedule; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors; D013997:Time Factors; D036542:Tomography, Spiral Computed; D016896:Treatment Outcome; D014481:United States
chemical_list: D018927:Anti-Asthmatic Agents; D000970:Antineoplastic Agents; D005938:Glucocorticoids; D011241:Prednisone