ABSTRACT
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.
Subject(s)
Adrenal Cortex Hormones/adverse effects , Asthma/drug therapy , Bone Density/drug effects , Bone Density/genetics , Calcification, Physiologic/drug effects , Calcification, Physiologic/genetics , Microtubule-Associated Proteins/genetics , Prednisone/adverse effects , Administration, Oral , Adrenal Cortex Hormones/administration & dosage , Bone Development/drug effects , Bone Diseases, Developmental/chemically induced , Bone Diseases, Developmental/genetics , Child , Child, Preschool , Dexamethasone/administration & dosage , Dexamethasone/pharmacology , Female , Gene Expression Regulation, Developmental/drug effects , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Osteoblasts/physiology , Polymorphism, Single Nucleotide , Prednisone/administration & dosage , Risk Factors , Tubulin/genetics , Tubulin/metabolismABSTRACT
BACKGROUND: To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. OBJECTIVE: We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. METHODS: We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). RESULTS: The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10(-8) (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10(-5)), rs2388639 (combined P = 8.56 × 10(-9)), and rs10044254 (combined P = 9.16 × 10(-8)) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. CONCLUSIONS: We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.