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 ×10−5 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.

Regulation of body length and bone mass by Gpr126/Adgrg6

“…FSK stimulates glucocorticoid production in the adrenal cortex by increasing cAMP (34), and glucocorticoids could negatively regulate osteoblast proliferation and differentiation (35). A bone mass decrease was found in children after long-term glucocorticoid treatment (36). Therefore, FSK may have had only limited effects on the body length and bone mass phenotype in Gpr126 deletion mice due to microenvironmental factors including IL-6 expression induced by FSK, offsetting the positive effect of FSK on osteoblasts in vivo.…”

Bone mineral density in children with acute lymphoblastic leukemia

“…Candidate gene studies have identified several single‐nucleotide polymorphisms (SNPs) associated with low BMD in patients with ALL, including those in the vitamin D receptor ( VDR ) 5′‐end ( Cdx‐2/GATA polymorphism) haplotype 3 ( P = .01), the genes encoding methylenetetrahydrofolate reductase (the MTHFR 677 thymine [T] allele) and methionine synthase reductase (the MTRR 66 guanine [G] allele; P ≤ .01 with 2 or more risk alleles), CRHR1 (the G allele of reference SNP rs1876828; P = .02 for boys), and RAPGEF5 (the T allele of rs6461639; P = .016) . However, there has been no genome‐wide analysis of low BMD in patients with ALL.…”

“…Candidate gene studies have identified several single-nucleotide polymorphisms (SNPs) associated with low BMD in patients with ALL, including those in the vitamin D receptor (VDR) 5 0 -end (Cdx-2/GATA polymorphism) haplotype 3 (P 5 .01), 8 the genes encoding methylenetetrahydrofolate reductase (the MTHFR 677 thymine [T] allele) and methionine synthase reductase (the MTRR 66 guanine [G] allele; P .01 with 2 or more risk alleles), 9 CRHR1 (the G allele of reference SNP rs1876828; P 5 .02 for boys), 10 and RAPGEF5 (the T allele of rs6461639; P 5 .016). 11 However, there has been no genome-wide analysis of low BMD in patients with ALL. Therefore, we evaluated clinical, pharmacokinetic, and genetic risk factors influencing BMD, especially those associated with a decline in BMD Z-scores during therapy, in children with ALL who received treatment on a contemporary protocol without cranial irradiation.…”

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation

“…There were 1409 results after removal of duplicates generated from the search strategy, but of these, only five were eligible for inclusion [29][30][31]. From the survey sent, two additional studies were discovered [32,33] (Fig. 1).…”

“…One study examined ADRs with inhaled short acting beta-2 agonists (SABA) [29], one analysed long acting beta-2 agonists (LABA) [30], three studies examined the use of corticosteroids [31][32][33], while no studies have examined ADRs occurring with either leukotriene receptor antagonists (LTA) or theophylline. For the SABA and LABA studies, a candidate gene approach was applied [29,30], whereas in the three corticosteroid studies, genome-wide association studies (GWAS) were used [31][32][33].…”