title: β2-Adrenergic receptor promoter haplotype influences the severity of acute viral respiratory tract infection during infancy: a prospective cohort study.
abstract: BACKGROUND
  Despite the significant interest in β2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections.
  
  
  METHODS
  To test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans.
  
  
  RESULTS
  There was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95% confidence interval: 0.36, 0.98). There was no similar protective relationship of haplotype CCA on severity of respiratory tract infections identified in Caucasians.
  
  
  CONCLUSIONS
  ADRB2 genotype may be predictive of severity of acute respiratory tract infections in African Americans, and potentially identify a subset of infants who may respond to beta-agonist therapy.
authors.affiliation: Center for Asthma & Environmental Health Sciences Research, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Suite 6100 Medical Center East, Nashville, TN, 37232, USA. pingsheng.wu@vanderbilt.edu.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Center for Asthma & Environmental Health Sciences Research, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Suite 6100 Medical Center East, Nashville, TN, 37232, USA. emma.larkin@vanderbilt.edu.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Larkin
authors.affiliation: Center for Asthma & Environmental Health Sciences Research, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Suite 6100 Medical Center East, Nashville, TN, 37232, USA. sara.reiss@vanderbilt.edu.
authors.forename: Sara S
authors.initials: SS
authors.lastname: Reiss
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine, 313 Oxford House, Nashville, TN, 37232, USA. kecia.carroll@vanderbilt.edu.
authors.forename: Kecia N
authors.initials: KN
authors.lastname: Carroll
authors.affiliation: Department of Genetics and Metabolism, Division of Genetics and Metabolism, Children's National Health System, 111 Michigan Avenue, NW, Washington, DC, 20010, USA. MSummar@childrensnational.org.
authors.forename: Marshall L
authors.initials: ML
authors.lastname: Summar
authors.affiliation: Center for Asthma & Environmental Health Sciences Research, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Suite 6100 Medical Center East, Nashville, TN, 37232, USA. patricia.minton@vanderbilt.edu.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Minton
authors.affiliation: Center for Asthma & Environmental Health Sciences Research, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Suite 6100 Medical Center East, Nashville, TN, 37232, USA. kim.woodward@vanderbilt.edu.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Woodward
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, 2525 West end Ave, Suite 1100, Nashville, TN, 37203, USA. zhouwen.liu@vanderbilt.edu.
authors.forename: Zhouwen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA. islamjy@live.unc.edu.
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Islam
authors.affiliation: Center for Asthma & Environmental Health Sciences Research, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Suite 6100 Medical Center East, Nashville, TN, 37232, USA. tina.hartert@vanderbilt.edu.
authors.forename: Tina V
authors.initials: TV
authors.lastname: Hartert
authors.affiliation: Division of Pediatric Allergy, Immunology and Pulmonary, Department of Pediatrics, Vanderbilt University School of Medicine, 2200 Children's Way, 11215 Doctor's Office Tower, Nashville, TN, 37232, USA. paul.moore@vanderbilt.edu.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Moore
mesh_terms: D001741:Black or African American / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D015810:Linkage Disequilibrium; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012141:Respiratory Tract Infections / Q000235:genetics* / Q000473:pathology* / Q000821:virology*; D018709:Statistics, Nonparametric; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: C553443:ADRB2 protein, human; D018343:Receptors, Adrenergic, beta-2