Heung-Woo Park^1,2, Szeman Tse^1,3, Wenjian Yang⁴, H. William Kelly⁵, Sue C. Kaste⁶, Ching-Hon Pui⁷, Mary V. Relling⁴, and Kelan G. Tantisira^1,8

¹The Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA ²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea ³Sainte-Justine University Hospital Center, Montreal, Quebec, Canada ⁴Departments of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA⁵Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, USA ⁶Departments of Radiological Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA ⁷Departments of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA ⁸Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

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^-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.

Keywords : Asthma; Acute lymphoblastic leukemia; Bone mineral density; Child; Glucocorticoid