Heung-Woo Park1, Bing Ge2, Szeman Tse3, Elin Grundberg4, Tomi Pastinen5, H William Kelly6, Kelan G Tantisira7. 1. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. 2. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada. 3. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Department of Pediatrics, Sainte-Justine University Health Center, University of Montreal, Montreal, Quebec, Canada. 4. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. 5. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Medical Genetics, McGill University, Montreal, Quebec, Canada. 6. Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM. 7. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Electronic address: kelan.tantisira@channing.harvard.edu.
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.
RCT Entities:
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.
Authors: Elin Grundberg; Veronique Adoue; Tony Kwan; Bing Ge; Qing Ling Duan; Kevin C L Lam; Vonda Koka; Andreas Kindmark; Scott T Weiss; Kelan Tantisira; Hans Mallmin; Benjamin A Raby; Olle Nilsson; Tomi Pastinen Journal: PLoS Genet Date: 2011-01-20 Impact factor: 5.917
Authors: Weiguo Zou; Matthew B Greenblatt; Nicholas Brady; Sutada Lotinun; Bo Zhai; Heather de Rivera; Anju Singh; Jun Sun; Steven P Gygi; Roland Baron; Laurie H Glimcher; Dallas C Jones Journal: J Exp Med Date: 2013-08-05 Impact factor: 14.307