Beta 2-adrenergic receptor polymorphisms and haplotypes are associated with airways hyperresponsiveness among nonsmoking men.
OBJECTIVE
To investigate the relationship of common single nucleotide polymorphisms (SNPs) of the beta(2)-adrenergic receptor (AR) gene at codons 16 and 27, and the intermediate phenotype of airways hyperresponsiveness.


METHODS
A case-control study in 543 white men (152 case patients and 391 control subjects), who were nested in an ongoing longitudinal cohort.


METHODS
Subjects were selected from the Normative Aging Study, an ongoing longitudinal cohort of healthy aging.


METHODS
Case patients were defined as those having a positive response to methacholine challenge testing. Control subjects were selected among those who did not have a diagnosis of asthma and who had no response to methacholine.


RESULTS
There was a trend for an association of the Arg16 SNP genotype with airways hyperresponsiveness (odds ratio, 1.25; 95% confidence interval, 0.96 to 1.64 [in an additive model]). In stratified analyses, the effect of the Arg16 variant was seen mainly among nonsmokers. Smokers had increased risks for airway hyperresponsiveness regardless of genotype at either SNP. Using a program to estimate haplotype frequencies, three common haplotypes were identified. Adjusting for age, baseline FEV(1), serum IgE level, and smoking status, the Gly16/Gln27 haplotype was negatively associated with airways hyperresponsiveness in the full complement of case patients and control subjects (score statistic, - 2.43; p = 0.02). The effect of the beta(2)-AR haplotypes was much stronger among lifelong nonsmokers, among whom the Gly16/Gln27 haplotype remained negatively associated with airways hyperresponsiveness (score statistic, - 3.114; p = 0.002), whereas the Arg16/Gln27 haplotype was positively associated with airways hyperresponsiveness (score statistic, 3.142; p = 0.002). No effects were seen among ever-smokers.


CONCLUSIONS
In this cohort of middle-aged to older white men, beta(2)-AR polymorphisms were associated with airways hyperresponsiveness, particularly among lifelong nonsmokers. Our results illustrate an instance in which greater power is obtained by performing haplotype analyses as opposed to single SNP analysis.
Litonjua
Augusto A
AA
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. augusto.litonjua@channing.harvard.edu
Silverman
Edwin K
EK
Tantisira
Kelan G
KG
Sparrow
David
D
Sylvia
Jody S
JS
Weiss
Scott T
ST
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012907:Smoking / Q000235:genetics
D018343:Receptors, Adrenergic, beta-2