title: beta2-Adrenergic receptor haplotypes in mild, moderate and fatal/near fatal asthma.
abstract: Excess beta2-agonist use in asthmatics has been associated with increased mortality and morbidity. The mechanisms responsible for these observations are unknown. We hypothesized that polymorphisms of the beta2-adrenergic receptor (beta2AR) at amino acid positions 16, 27, and 164, which are known to alter receptor functions in vitro, may predispose asthmatics to fatal/near-fatal asthma and/or modify asthma severity. In preliminary studies we found significant differences in allele frequencies due to ethnic background: Caucasian, Black, Asian Gly16 = 0.61, 0.50, 0.40 and Gln27 = 0.57, 0. 73, 0.80, respectively. beta2AR genotyping was performed on DNA from Caucasians classified as nonasthmatic/nonatopic (n = 84), fatal/near-fatal asthmatics (n = 81) and mild/moderate asthmatics (n = 86). No polymorphism or haplotype was found to be associated with fatal/near-fatal asthma. However, the Gly16/Gln27 haplotype, which undergoes enhanced downregulation in vitro, was substantially more prevalent in moderate asthmatics than in mild asthmatics (p = 0.003, odds ratio = 3.1). We conclude that the beta2AR genotype is not a major determinant of fatal or near-fatal asthma. Furthermore, allele frequency variation among ethnic groups must be considered in clinical studies of beta2AR polymorphisms in asthma.
authors.affiliation: Respiratory Health Network of Centres of Excellence, University of British Columbia Pulmonary Research Laboratory, St. Paul's Hospital, Vancouver, Canada.
authors.forename: T D
authors.initials: TD
authors.lastname: Weir
authors.forename: N
authors.initials: N
authors.lastname: Mallek
authors.forename: A J
authors.initials: AJ
authors.lastname: Sandford
authors.forename: T R
authors.initials: TR
authors.lastname: Bai
authors.forename: N
authors.initials: N
authors.lastname: Awadh
authors.forename: J M
authors.initials: JM
authors.lastname: Fitzgerald
authors.forename: D
authors.initials: D
authors.lastname: Cockcroft
authors.forename: A
authors.initials: A
authors.lastname: James
authors.forename: S B
authors.initials: SB
authors.lastname: Liggett
authors.forename: P D
authors.initials: PD
authors.lastname: Paré
mesh_terms: D000318:Adrenergic beta-Agonists / Q000009:adverse effects; D000328:Adult; D000483:Alleles; D000596:Amino Acids / Q000235:genetics; D018927:Anti-Asthmatic Agents / Q000009:adverse effects; D044466:Asian People / Q000235:genetics; D001249:Asthma / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D044383:Black People / Q000235:genetics; D002423:Cause of Death; D004247:DNA / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005006:Ethnicity; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D005973:Glutamine / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic / Q000235:genetics; D015995:Prevalence; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D000318:Adrenergic beta-Agonists; D000596:Amino Acids; D018927:Anti-Asthmatic Agents; D011943:Receptors, Adrenergic, beta; D005973:Glutamine; D004247:DNA; D005998:Glycine