Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts

Background Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA). Objective We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma. Methods We first performed a gene-by-OCS...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology 2015-11, Vol.136 (5), p.1240-1246.e8
Main Authors: Park, Heung-Woo, MD, PhD, Ge, Bing, MSc, Tse, Szeman, MDCM, Grundberg, Elin, PhD, Pastinen, Tomi, MD, PhD, Kelly, H. William, PharmD, Tantisira, Kelan G., MD, MPH
Format: Article
Language:English
Subjects:
Administration, Oral
Adrenal Cortex Hormones - administration & dosage
Adrenal Cortex Hormones - adverse effects
Age
Allergy and Immunology
Asthma
Asthma - drug therapy
Body mass index
Bone Density - drug effects
Bone Density - genetics
Bone Development - drug effects
Bone Diseases, Developmental - chemically induced
Bone Diseases, Developmental - genetics
bone mineral density
Calcification, Physiologic - drug effects
Calcification, Physiologic - genetics
Child
Child, Preschool
corticosteroids
Dexamethasone - administration & dosage
Dexamethasone - pharmacology
Female
Gene expression
Gene Expression Regulation, Developmental - drug effects
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Genomes
Humans
Male
Microtubule-Associated Proteins - genetics
Osteoblasts - physiology
Osteoporosis
Polymorphism, Single Nucleotide
Prednisone - administration & dosage
Prednisone - adverse effects
Regression analysis
Risk Factors
Software
Tubulin - genetics
Tubulin - metabolism
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Summary:Background Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA). Objective We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma. Methods We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis -regulatory effects on dexamethasone-induced gene expression in osteoblasts. Results We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. The rs9896933 variant met the criteria for genome-wide significance ( P  = 3.15 × 10−8 in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant ( P  = 2.74 × 10−4 in the GWAS) showed strong cis -regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblasts ( P  = 8.64 × 10−4 ). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased. Conclusions We have identified 2 novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.
ISSN:0091-6749
1097-6825
1097-6825
DOI:10.1016/j.jaci.2015.04.014