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