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ß₂-Adrenergic Receptor Polymorphisms and Haplotypes Are Associated With Airways Hyperresponsiveness Among Nonsmoking Men^*

^* From the Channing Laboratory (Drs. Litonjua, Silverman, Tantisira, and Weiss, and Ms. Sylvia), Department of Medicine, Brigham and Women’s Hospital, Boston; and the Normative Aging Study (Dr. Sparrow), Veterans Affairs Medical Center, Boston, MA.

Correspondence to: Augusto A. Litonjua, MD, FCCP, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115; e-mail: augusto.litonjua{at}channing.harvard.edu

Study objective: To investigate the relationship of common single nucleotide polymorphisms (SNPs) of the ß₂-adrenergic receptor (AR) gene at codons 16 and 27, and the intermediate phenotype of airways hyperresponsiveness.

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

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

Participants: 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 FEV₁, 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 ß₂-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, ß₂-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.

Key Words: ß₂-adrenergic receptor gene • genetic • haplotype • polymorphisms • smoking

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