title: Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during longacting β agonist treatment in a multiethnic asthma population: a genetic study.
abstract: BACKGROUND
  Severe adverse life-threatening events associated with longacting β agonist (LABA) use have caused the US Food and Drug Administration (FDA) to review the safety of these drugs, resulting in a boxed warning and a mandatory safety study in 46 800 patients with asthma. Identification of an at-risk, susceptible subpopulation on the basis of predictive biomarkers is crucial for understanding LABA safety. The β2-adrenergic receptor gene (ADRB2) contains a common, non-synonymous single nucleotide polymorphism, Gly16Arg, that is unlikely to account for the rare, life-threatening events seen with LABA use. We hypothesise that rare ADRB2 variants modulate therapeutic responses to LABA therapy and contribute to rare, severe adverse events.
  
  
  METHODS
  In this genetic study, ADRB2 was sequenced in 197 African American, 191 non-Hispanic white, and 73 Puerto Rican patients. Sequencing identified six rare variants, which were genotyped in 1165 patients with asthma. The primary hypothesis was that severe asthma exacerbations requiring hospital admission were associated with rare ADRB2 variants in patients receiving LABA therapy. This outcome was assessed overall and by ethnic group. Replication was done in 659 non-Hispanic white patients with asthma.
  
  
  RESULTS
  Patients receiving LABA with a rare ADRB2 variant had increased asthma-related hospital admissions (15 [44%] of 34 patients with rare variant vs 121 [22%] of 553 patients with common ADRB2 alleles admitted to hospital in past 12 months; meta-analysis for all ethnic groups, p=0·0003). Specifically, increases in hospital admission rates were recorded in LABA-treated non-Hispanic white patients with the rare Ile 164 allele compared with non-Hispanic white patients with the common allele (odds ratio [OR] 4·48, 95% CI 1·40-13·96, p=0·01) and African American patients with a 25 bp promoter polynucleotide insertion, -376ins, compared with African American patients with the common allele (OR 13·43, 95% CI 2·02-265·42, p=0·006). The subset of non-Hispanic white and African American patients receiving LABAs with these rare variants had increased exacerbations requiring urgent outpatient health-care visits (non-Hispanic white patients with or without the rare Ile 164 allele, 2·6 [SD 3·5] vs 1·1 [2·1] visits, p<0·0001; and African American patients with or without the rare insertion, 3·7 [4·6] vs 2·4 [3·4] visits, p=0·01), and more frequently were treated with chronic systemic corticosteroids (OR 4·25, 95% CI 1·38-14·41, p=0·01, and 12·83, 1·96-251·93, p=0·006). Non-Hispanic white patients from the primary and replication cohorts with the rare Ile 164 allele were more than twice as likely as Thr 164 homozygotes to have uncontrolled, persistent symptoms during LABA treatment (p=0·008-0·04).
  
  
  CONCLUSIONS
  The rare ADRB2 variants Ile164 and -376ins are associated with adverse events during LABA therapy and should be evaluated in large clinical trials including the current FDA-mandated safety study.
  
  
  BACKGROUND
  US National Institutes of Health.
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Ortega
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Hawkins
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Moore
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Hastie
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ampleford
authors.affiliation: Department of Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Busse
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.affiliation: Hospital Episcopal San Lucas, Ponce School of Medicine, Ponce, Puerto Rico.
authors.forename: Domingo
authors.initials: D
authors.lastname: Chardon
authors.affiliation: Department of Pathobiology and Respiratory Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.affiliation: Hospital Episcopal San Lucas, Ponce School of Medicine, Ponce, Puerto Rico.
authors.forename: Federico
authors.initials: F
authors.lastname: Montealegre
authors.affiliation: Asthma Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Wenzel
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Peters
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Meyers
authors.affiliation: Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. Electronic address: ebleeck@wakehealth.edu.
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Bleecker
mesh_terms: D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D006630:Hispanic or Latino / Q000235:genetics*; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D018343:Receptors, Adrenergic, beta-2