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Polymorphisms in the Muscarinic Receptor 1 Gene Confer Susceptibility to Asthma in Japanese Subjects

First Department of Medicine and Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

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

Rationale: The human cholinergic receptor muscarinic-1 (CHRM1) is widely distributed in the lungs. In patients with asthma, CHRM1 may be involved in airway constriction, airway epithelial cell proliferation, and airway inflammation. The CHRM1 gene is located on chromosome 11q13, which is one of the candidate loci for asthma and atopy.

Objectives: To determine the role of the CHRM1 gene polymorphisms in asthma.

Methods: We studied nine single-nucleotide polymorphisms (–18379G > A, –9697C > T, –6965T > C, –4953A > G, +267A > C, +1353C > T, +3970C > G, +5418C > G, and +5455G > T) in a case-control study using 326 patients with asthma and 333 healthy control subjects. We also examined functional consequences of the –9697C > T and –4953A > G polymorphisms at the regulatory region using an mRNA reporter assay.

Measurements and Main Results: Two common single-nucleotide polymorphisms (–9697C > T and –4953A > G) were associated with asthma. The odds ratio for the TT homozygotes at the –9697C > T polymorphism was 0.29 compared with the CC homozygotes (95% confidence interval, 0.12–0.73; p = 0.008), and the odds ratio for the GG homozygotes at the –4953A > G polymorphism was 1.86 compared with the AA homozygotes (95% confidence interval, 1.04–3.34; p = 0.038). Haplotype analysis showed that the –9697T/–6965T/–4953A haplotype was associated with a lower risk of asthma (p = 0.00055) and the –9697C/–6965T/–4953G haplotype was associated with an increased risk of asthma (p = 0.020). The –9697T/–4953A haplotype was also associated with lower luciferase activity in vitro compared with the –9697C/–4953G haplotype.

Conclusions: This study, together with an in vitro functional study, suggests that the CHRM1 gene is an important susceptibility locus for asthma on chromosome11q13.

Key Words: case-control studies • IgE • muscarinic cholinergic receptor-1 • single-nucleotide polymorphism

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Genetic studies repeatedly have linked asthma and asthma-related phenotypes to chromosome 11q13, on which several biological candidate genes are located. What This Study Adds to the Field Gene coding the human cholinergic receptor muscarinic-1 (CHRM1) is an important susceptibility locus for asthma at chromosome 11q13.

 

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