Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma in Japanese subjects
Polymorphisms in the muscarinic receptor 1 gene confer susceptibility to asthma in Japanese subjects
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DOI：
10.1164/rccm.200601-081oc
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发表时间：
2006-11-15
影响因子：
24.7
通讯作者：
Nishimura, Masaharu
中科院分区：
文献类型：
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作者：
Maeda, Yukiko;Hizawa, Nobuyuki;Nishimura, Masaharu
理论基础：人类胆碱能受体M受体-1(CHRM1)广泛分布于肺部。在哮喘患者中，CHRM1可能参与了气道收缩、气道上皮细胞增殖和气道炎症。CHRM1基因位于染色体11q13上，是哮喘和特应性疾病的候选基因之一。目的：探讨CHRM1基因多态性在哮喘发病中的作用。方法：采用病例对照研究方法，对326例哮喘患者和333例健康对照进行了9个单核苷酸多态(-18379G>；A、-9697C>；C、-6965T>；G、+267A>；G、+1353C>；T、+3970C>；G、+5418C>；G和+5455G>；T)的研究。我们还使用信使核糖核酸报告分析检测了调节区-9697C>；T和-4953A>；G多态的功能后果。测量和主要结果：两个常见的单核苷酸多态(-9697C>；T和-4953A>；G)与哮喘相关。TT纯合子与CC纯合子(95%可信区间，0.12~0.73；P=0.008)、GG纯合子与AA纯合子(95%可信区间，1.04~3.34；P=0.038)的优势比分别为0.29和1.86。单倍型分析显示-9697T/-6965T/-4953A单倍型与哮喘风险降低相关(p=0.00055)，-9697C/-6965T/-4953G单倍型与哮喘风险增加相关(p=0.020)。-9697T/-4953A单倍型与-9697C/-4953G单倍型相比，其体外荧光素酶活性也较低。结论：CHRM1基因与体外功能研究相结合，提示CHRM1基因是11q13号染色体上一个重要的哮喘易感基因。
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-nucleoticle 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 chromosome 11q13.