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A Functional Polymorphism in the RANTES Gene Promoter Is Associated with the Development of Late-Onset Asthma

First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan

Correspondence and requests for reprints should be addressed to Nobuyuki Hizawa, First Department of Medicine, Hokkaido University School of Medicine, Kita-Ku, N-15 N-7, Sapporo, Japan 060-8638. E-mail: nhizawa{at}med.hokudai.ac.jp

The CC chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES) attracts eosinophils, basophils, and T cells during inflammation and immune response, indicating a possible role for this chemokine in asthma. Both the -403A and -28G alleles of the RANTES promoter region exhibit significantly enhanced promoter activity in reporter constructs in vitro. We therefore investigated the genetic influence of these alleles on the development of asthma using case-control analysis in a Japanese population (298 patients with asthma and 311 control subjects). Given the evidence for heterogeneity of asthma according to age at onset, we divided patients with asthma into three subgroups: 117 late-onset patients with asthma (onset at more than 40 years of age), 83 middle-onset patients with asthma (onset at 20 to 40 years of age), and 98 early-onset patients with asthma (onset at less than 20 years of age). The -28G allele was significantly associated with late-onset asthma (odds ratio = 2.033; 95% confidence interval, 1.379–2.998; corrected p < 0.0025) but was not associated with the other two asthma subgroups. The -403A allele was not associated with any of the asthma subgroups. Further evidence of the importance of the -28G allele was a significant increase in the production of RANTES in vitro in individuals who carried this allele. Our findings suggest that, among Japanese, the -28G allele of the RANTES promoter region confers susceptibility to late-onset asthma.

Key Words: late-onset asthma • RANTES • single nucleotide polymorphism (SNP)

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