title: Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts.
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.
authors.affiliation: 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.
authors.forename: Heung-Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: 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.
authors.forename: Szeman
authors.initials: S
authors.lastname: Tse
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.affiliation: 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.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM.
authors.forename: H William
authors.initials: HW
authors.lastname: Kelly
authors.affiliation: 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.
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
mesh_terms: D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000009:adverse effects*; D001249:Asthma / Q000188:drug therapy*; D015519:Bone Density / Q000187:drug effects* / Q000235:genetics*; D001846:Bone Development / Q000187:drug effects; D001848:Bone Diseases, Developmental / Q000139:chemically induced / Q000235:genetics; D002113:Calcification, Physiologic / Q000187:drug effects* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010006:Osteoblasts / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D008869:Microtubule-Associated Proteins; C418662:TBCD protein, human; C582625:TUBG1 protein, human; D014404:Tubulin; D003907:Dexamethasone; D011241:Prednisone
keywords: Asthma; bone mineral density; child; corticosteroids