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.
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This work was supported by the NIH Pharmacogenomics Research Network, U01 HL65899 and U01 GM92666; and by NIH NHLBI R01 HL092197, NINR R01 NR013391 and NCI grants CA 142665, and CA 21765; and by the American Lebanese Syrian Associated Charities (ALSAC). The Childhood Asthma Management Program is supported by contracts NO1-HR-16044, 16045, 16046, 16047, 16048, 16049, 16050, 16051 and 16052 with the National Heart, Lung, and Blood Institute and General Clinical Research Center grants M01RR00051, M01RR0099718–24, M01RR02719–14 and RR00036 from the National Center for Research Resources.
The authors directed and had access to all the analyses and the full clinical and genetic database, wrote all drafts of the report, decided to publish the results and attest for the accuracy and completeness of the data.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
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Park, H., Tse, S., Yang, W. et al. A genetic factor associated with low final bone mineral density in children after a long-term glucocorticoids treatment. Pharmacogenomics J 17, 180–185 (2017) doi:10.1038/tpj.2015.92