Influence of beta2-adrenoceptor gene polymorphisms on beta2-adrenoceptor-mediated responses in human lung mast cells.
OBJECTIVE
Previous studies have shown that beta(2)-adrenoceptor-mediated responses in human lung mast cells are highly variable. The aims of the present study were to establish whether polymorphisms of the beta (2)-adrenoceptor gene (ADRB2) influence this variability in (a) beta(2)-adrenoceptor-mediated inhibition and (b) desensitization of beta(2)-adrenoceptor-mediated responses in human lung mast cells.


METHODS
Mast cells were isolated from human lung tissue. The inhibitory effects of the beta-adrenoceptor agonist, isoprenaline (10(-10)-10(-5) M), on IgE-mediated histamine release from mast cells were determined (n=92). Moreover, the inhibitory effects of isoprenaline were evaluated following a desensitizing treatment involving long-term (24 h) incubation of mast cells with isoprenaline (10(-6) M) (n=65). A potential influence of polymorphisms on these functional responses was determined by genotyping 11 positions, in the promoter and coding regions, of ADRB2 previously reported as polymorphic.


RESULTS
There was no influence of any of the polymorphic positions of ADRB2 on the potency of isoprenaline to inhibit histamine release from mast cells with the exception of position 491C>T (Thr164Ile). There was no influence of any of the polymorphic positions of ADRB2 on the extent of desensitization of the isoprenaline-mediated response following a desensitizing treatment except for position 46G>A (Gly16Arg). Analyses at the haplotype level indicated that there was no influence of haplotype on beta (2)-adrenoceptor-mediated responses in mast cells.


CONCLUSIONS
These data indicate that certain polymorphisms in ADRB2 influence beta(2)-adrenoceptor-mediated responses in human lung mast cells.
Kay
L J
LJ
Academic Unit of Molecular Pharmacology, University of Sheffield, The Royal Hallamshire Hospital (Floor M), Sheffield, S Yorks S10 2JF, UK.
Rostami-Hodjegan
A
A
Suvarna
S K
SK
Peachell
P T
PT
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D003888:Desensitization, Immunologic; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D016366:Open Reading Frames; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D007073:Immunoglobulin E; D006632:Histamine; D007545:Isoproterenol