GENETIC POLYMORPHISMS OF THE BETA(2)-ADRENERGIC RECEPTOR IN NOCTURNALAND NONNOCTURNAL ASTHMA - EVIDENCE THAT GLY16 CORRELATES WITH THE NOCTURNAL PHENOTYPE

Nocturnal asthma represents a unique subset of patients with asthma wh o experience worsening symptoms and airflow obstruction at night, The basis for this phenotype of asthma is not known, but beta(2)-adrenergi c receptors (beta(2)AR) are known to downregulate overnight in nocturn al asthmatics but not normal subjects or nonnocturnal asthmatics, We h ave recently delineated three polymorphic loci within the coding block of the beta(2)AR which alter amino acids at positions 16, 27, and 164 and impart specific biochemical and pharmacologic phenotypes to the r eceptor, In site-directed mutagenesis/recombinant expression studies w e have found that glycine at position 16 (Gly16) imparts an accelerate d agonist-promoted downregulation of beta(2)AR as compared to arginine at this position (Arg16), We hypothesized that Gly16 might be overrep resented in nocturnal asthmatics and thus determined the beta(2)AR gen otypes of two well-defined asthmatic cohorts: 23 nocturnal asthmatics with 34+/-2% nocturnal depression of peak expiratory flow rates, and 2 2 nonnocturnal asthmatics with virtually no such depression (2.3+/-0.8 %). The frequency of the Gly16 allele was 80.4% in the nocturnal group as compared to 52.2% in the nonnocturnal group, while the Arg16 allel e was present in 19.6 and 47.8%, respectively, This overrepresentation of the Gly16 allele in nocturnal asthma was significant at P = 0.007 with an odds ratio of having nocturnal asthma and the Gly16 polymorphi sm being 3.8. Comparisons of the two cohorts as to homozygosity for Gl y16, homozygosity for Arg16, or heterozygosity were also consistent wi th segregation of Gly16 with nocturnal asthma, There was no difference in the frequency of polymorphisms at loci 27 (Gln27 or Glu27) and 164 (Thr164 or Ile164) between the two groups. Thus the Gly16 polymorphis m of the beta(2)AR, which imparts an enhanced downregulation of recept or number, is overrepresented in nocturnal asthma and appears to be an important genetic factor in the expression of this asthmatic phenotyp e.