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Association Between Nonspecific Airway Hyperresponsiveness and Arg16Gly ß₂-Adrenergic Receptor Gene Polymorphism in Asymptomatic Healthy Japanese Subjects^*

^* From the First Department of Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Correspondence to: Nobuyuki Hizawa, MD, First Department of Medicine, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan; e-mail: nhizawa{at}med.hokudai.ac.jp

Abstract

Background: Nonspecific airway hyperresponsiveness (AHR), a cardinal feature of asthma, is thought to result from several genetic and environmental factors. Asymptomatic AHR in nonasthmatic healthy subjects might be a risk factor for the development of asthma. Genetic variations in codons 16 and 27 of the human ß₂-adrenergic receptor (ß₂-AR) alter receptor function in vitro and are associated with various asthma-related phenotypes, including asthma severity and AHR. To date, however, few reports have examined the impact of ß₂-AR gene polymorphism on AHR in asymptomatic healthy subjects.

Objective: To determine whether polymorphism of the ß₂-AR gene (Arg16Gly and Gln27Glu) might influence nonspecific AHR in asymptomatic healthy Japanese subjects.

Design and participants: A cohort of 120 asymptomatic healthy subjects was analyzed using a stepwise linear regression model. Nonspecific airway responsiveness was measured using a continuous methacholine inhalation method (Astograph; Chest; Tokyo, Japan). We used values of the cumulative dose of inhaled methacholine measured at the inflection point at which respiratory conductance starts to decrease (Dmin) as an index of AHR. Genotyping to identify polymorphisms at codons 16 and 27 was conducted using an assay combining kinetic real-time quantitative polymerase chain reaction with allele-specific amplification.

Results: The Gly16Gly genotype was associated with lower Dmin values. The log Dmin value of asymptomatic healthy subjects carrying the Arg16 allele (Arg16/Arg or Arg16/Gly, n = 90) was 1.09 ± 0.56 (mean ± SD), while those homozygous for the Gly16 allele (n = 30) yielded a log Dmin value of 0.85 ± 0.56 (p < 0.05).

Conclusion: This study indicates that a specific ß₂-AR polymorphism at codon 16 might be a genetic determinant of AHR, as judged by methacholine-induced bronchoconstriction in asymptomatic healthy subjects.

Key Words: airway hyperresponsiveness • asymptomatic healthy subject • ß₂-adrenergic receptor • polymorphism

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