Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma
Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma
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DOI：
10.1164/ajrccm.160.3.9812024
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发表时间：
1999-09-01
影响因子：
24.7
通讯作者：
Drazen, JM
中科院分区：
文献类型：
--
作者：
Burchard, EG;Silverman, EK;Drazen, JM
最近以家族为基础的研究揭示了人类染色体5 q31与哮喘诊断、血清IgE水平升高和支气管高反应性相关的证据。在该区域的候选基因中有编码人白细胞介素-4（IL-4）的基因。我们推断，该基因也可以作为与哮喘严重程度相关的候选基因，如FEV，在停止支气管扩张剂治疗时测量。为了验证这一假设，我们研究了大量哮喘患者（确定不考虑遗传特征），IL-4启动子区（C-589 T）的遗传变异与哮喘严重程度（如FEV 1所示）之间的关联。我们使用聚合酶链反应扩增，然后用BsmF 1限制性消化来分配IL-4启动子C-589 T位点的基因型。我们比较了772例不同严重程度的白种人和非洲裔美国人哮喘患者在该位点的基因型，并采用多元回归分析将基因型结果与FEV，。在白色个体中，C-589 T IL-4启动子基因型（TT）的纯合存在与FEV 1低于预测值的50%相关（p = 0.013; OR，1.44; 95%CI：1.09至1.90）。TT基因型受试者的平均FEV 1（%预测值）值比该位点野生型（CC）基因型受试者低4.5%。具有CC或CT基因型的白色患者的FEV，值分布广泛，而TF基因型与低FEV，值的窄分布相关。非裔美国人哮喘患者T等位基因频率（0.544）显著高于白色哮喘患者（0.183）（p = 1 × 10（-23））。这些数据首次提供了哮喘患者FEV 1与任何位点遗传决定因素相关的证据。我们的数据与哮喘FEV 1是多因素影响的结果的观点一致，其中一个因素是IL-4 C-589 T基因座的基因型。该位点与白色哮喘受试者的肺功能小而显著的降低有关。
Recent family-based studies have revealed evidence for linkage of human chromosome 5q31 to the diagnosis of asthma, elevated serum IgE levels, and bronchial hyperresponsiveness. Among the candidate genes in this region is the gene encoding for human interleukin-4 (IL-4). We reasoned that this gene could also serve as a candidate gene with respect to asthma severity as indicated by the FEV, measured when bronchodilator treatment was withheld. To test this hypothesis, we examined a large population of patients with asthma (ascertained without respect to genetic characteristics), for associations between a genetic variant in the IL-4 promoter region (C-589T) and asthma severity, as indicated by FEV1. We used amplification by the polymerase chain reaction followed by BsmF1 restriction digestion to assign genotypes at the IL-4 promoter C-589T locus. We compared genotypes at this locus in 772 Caucasian and African American patients with asthma of varying severity, and we used multiple regression analysis to relate genotypic findings to FEV,. Among white individuals, the homozygous presence of the C-589T IL-4 promoter genotype (TT) was associated with a FEV1 below 50% of predicted (p = 0.013; OR, 1.44; 95% CI: 1.09 to 1.90). Subjects with the TT genotype had mean FEV1 (% predicted) values 4.5% lower than those of subjects with the wild-type (CC) genotype at this locus. FEV, values of white patients with a CC or CT genotype were broadly distributed, whereas the TF genotype was associated with a narrow distribution of low FEV, values. The frequency of the T allele was significantly greater (p = 1 x 10(-23)) among African American asthmatics (0.544) than among white asthmatics (0.183). These data provide the first evidence associating FEV1 in patients with asthma and genetic determinants at any locus. Our data are consistent with the idea that the FEV1 in asthma is the result of multiple factors; one of these factors is the genotype at the IL-4 C-589T locus. This locus is associated with a small but significant decrement in pulmonary function among white asthmatic subjects.