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.
Subscribe to Journal
Get full journal access for 1 year
only $104.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Buehring B, Viswanathan R, Binkley N, Busse W . Glucocorticoid-induced osteoporosis: an update on effects and management. J Allergy Clin Immunol 2013; 132: 1019–1030.
Tsampalieros A, Gupta P, Denburg MR, Shults J, Zemel BS, Mostoufi-Moab S et al. Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome. J Bone Miner Res 2013; 28: 480–488.
Rousseau-Nepton I, Lang B, Rodd C . Long-term bone health in glucocorticoid-treated children with rheumatic diseases. Curr Rheumatol Rep 2013; 15: 315.
Kaste SC, Jones-Wallace D, Rose SR, Boyett JM, Lustig RH, Rivera GK et al. Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development. Leukemia 2001; 15: 728–734.
Kelly HW, Van Natta ML, Covar RA, Tonascia J, Green RP, Strunk RC . Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood Asthma Management Program (CAMP) study. Pediatrics 2008; 122: e53–e61.
Brown JJ, Zacharin MR . Proposals for prevention and management of steroid induced osteoporosis in children and adolescents. J Paediatr Child Health 2005; 41: 553–557.
Jones TS, Kaste SC, Liu W, Cheng C, Yang W, Tantisira KG et al. CRHR1 polymorphisms predict bone density in survivors of acute lymphoblastic leukemia. J Clin Oncol 2008; 26: 3031–3037.
Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000; 343: 1054–1063.
Tse SM, Kelly HW, Litonjua AA, Van Natta ML, Weiss ST, Tantisira KG . Corticosteroid use and bone mineral accretion in children with asthma: effect modification by vitamin D. J Allergy Clin Immunol 2012; 130: 53–60.
Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004; 104: 2690–2696.
Stanisavljevic S, Babcock AL . Fractures in children treated with methotrexate for leukemia. Clin Orthop Relat Res 1977; 125: 139–144.
Sala A, Barr RD . Osteopenia and cancer in children and adolescents: the fragility of success. Cancer 2007; 109: 1420–1431.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ . Exploiting gene-environment interaction to detect genetic associations. Hum Hered 2007; 63: 111–119.
Bachrach LK . Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metab 2001; 12: 22–28.
Weinstein RS . Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord 2001; 2: 65–73.
Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ et al. Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest 2006; 116: 2152–2160.
Teitelbaum SL . The osteoclast and its unique cytoskeleton. Ann N Y Acad Sci 2011; 1240: 14–17.
Chellaiah MA . Regulation of actin ring formation by rho GTPases in osteoclasts. J Biol Chem 2005; 280: 32930–32943.
Faccio R, Teitelbaum SL, Fujikawa K, Chappel J, Zallone A, Tybulewicz VL et al. Vav3 regulates osteoclast function and bone mass. Nat Med 2005; 11: 284–290.
Rebhun JF, Castro AF, Quilliam LA . Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction. J Biol Chem 2000; 275: 34901–34908.
Zou W, Izawa T, Zhu T, Chappel J, Otero K, Monkley SJ et al. Talin1 and Rap1 are critical for osteoclast function. Mol Cell Biol 2013; 33: 830–844.
He M, Wang Y, Li W . PPI finder: a mining tool for human protein-protein interactions. PLoS One 2009; 4: e4554.
Human protein-protein interaction mining tool. Steroid-regulated promoters. http://liweilab.genetics.ac.cn/tm/search.php?st=gn&gn=steroid-regulated%20promoters&ti=9606&tn=250&sot=&pg=5.
Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 2012; 44: 491–501.
Zhang L, Choi HJ, Estrada K, Leo PJ, Li J, Pei YF et al. Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Hum Mol Genet 2014; 23: 1923–1933.
Kemp JP, Medina-Gomez C, Estrada K St, Pourcain B, Heppe DH, Warrington NM et al. Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment. PLoS Genet 2012; 10: e1004423.
Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 2012; 22: 1790–1797.
Regulome DB . Data supporting chr7:22186954 (rs6461639). http://regulome.stanford.edu.
SNAP, SNP Annotation and Proxy Search. https://www.broadinstitute.org/mpg/snap/ldsearch.php.
SCAN, SNP and CNV Annotation Database. http://www.scandb.org/newinterface/index_v1.html.
dbSNP. Rs6461639. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=6461639.
Lanktree MB, Hegele RA . Gene-gene and gene-environment interactions: new insights into the prevention, detection and management of coronary artery disease. Genome Med 2009; 1: 28.
Keller MC . Gene x environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution. Biol Psychiatry 2014; 75: 18–24.
Lazzeroni LC, Lu Y, Belitskaya-Lévy I . P-values in genomics: apparent precision masks high uncertainty. Mol Psychiatry 2014; 19: 1336–1340.
Bosker FJ, Hartman CA, Nolte IM, Prins BP, Terpstra P, Posthuma D et al. Poor replication of candidate genes for major depressive disorder using genome-wide association data. Mol Psychiatry 2011; 16: 516–532.
Nilsson D, Andiappan AK, Halldén C, Tim CF, Säll T, Wang de Y et al. Poor reproducibility of allergic rhinitis SNP associations. PLoS One 2013; 8: e53975.
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
About this article
Cite this article
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). https://doi.org/10.1038/tpj.2015.92