中国中部地区哮喘患儿8个常见单核苷酸多态性的相关性及基因间相互作用
2010/07/06
背景：哮喘是一种常见的多基因疾病，与多个基因与环境因素之间复杂的相互作用有关。研究基因之间的相互影响有助于从新的角度理解哮喘的发病机理和治疗方法。
目的：在中国哮喘儿童中，研究5个与哮喘发病有关的候选基因内的8个单核苷酸多态位点与哮喘发病的单独及联合作用。
方法：我们检测了5个关键的哮喘易感基因内的8个单核苷酸多态性(SNPs)，对479位中国儿童（252名哮喘患儿和227名健康受试者）进行了单个SNP相关性研究、单倍体分析和基因间相互作用的分析。采用聚合酶链反应限制性片段长度多态性进行基因分型。采用SHEsis软件进行单倍型分析。多因素降维处理方法（MDR）分析基因间相互作用。
结果：哮喘患者与对照组之间，在基因型和等位基因频率中，存在显著的IL-13 R130Q 与 IL-13 C1923T差异。此外，IL-13 R130Q的A等位基因与IL-13 C1923T的T等位基因都与哮喘的危险程度有明显的相关性（分别为：OR：1.59，95%CI：1.20-2.09，P：0.0010；OR：1.57，95%CI：1.19-2.08，P：0.0014）。通过单体型分析，组成IL-13 R130Q 与 IL-13 C1923T的G-A和T-A以及组成IL-4R I75V 与 IL-4R Q576R的G-A 和A-A都与哮喘有显著相关性（P<0.05）。通过MDR法，采用最佳6位点模型，结果显示哮喘相关的IL-4 -C33T、IL-13 R130Q、 IL-4R I75V、IL-4R Q576R、STAT6 C2892T和 CD14 -C159T对哮喘风险的影响存在显著的基因-基因间相互作用（采用1000倍排列检定，OR：4.43，95%CI：1.30-15.04，P<0.001）。
结论：本研究提示IL-13基因的变异在中国中部地区儿童哮喘的发病过程中具有重要作用。此外，IL-4 -C33T, IL-13 R130Q, IL-4R I75V, IL-4R Q576R, STAT6 C2892T及CD14 -C159T等6个基因之间的相互作用可能增加个体对哮喘的易感性，与哮喘的发病有关。
（林江涛 审校）
Wu X, et al. J Asthma. 2010 Apr;47(3):238-244.
Association and gene-gene interactions of eight common single-nucleotide polymorphisms with pediatric asthma in middle china.
Wu X, Li Y, Chen Q, Chen F, Cai P, Wang L, Hu L.
Department of Clinical Laboratory, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Abstract
BACKGROUND: Asthma is a common polygenic disease, caused by complex interactions between multiple genes and environmental factors. Study of the gene-gene interactions would contribute to a new insight into the pathogenesis and therapeutics of asthma.
OBJECTIVE: To evaluate the single and combined associations of eight single-nucleotide polymorphisms loci in five candidate genes with the development of asthma in Chinese children.
METHODS: We examined eight single-nucleotide polymorphisms (SNPs) in five key asthma susceptibility genes and performed single SNP association study, haplotype analysis, and gene-gene interactions analysis in 479 Chinese children, including 252 asthmatic subjects and 227 healthy controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Haplotype analysis was detected by SHEsis software. Gene-gene interactions were tested using the multifactor dimensionality reduction (MDR) method.
RESULTS: There were significant differences of interleukin (IL)-13 R130Q and IL-13 C1923T in genotype and allele frequency distributions between the asthmatic group and control group. Furthermore, the A allele of IL-13 R130Q and the T allele of IL-13 C1923T were significantly associated with increased risk of asthma (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.20-2.09, p = .0010; OR = 1.57, 95% CI 1.19-2.08, p = .0014, respectively). By haplotype analysis, the C-G and T-A haplotypes consisting of IL-13 C1923T and IL-13 R130Q and the G-A and A-A haplotypes consisting of IL-4Ralpha I75V and IL-4Ralpha Q576R were significantly associated with asthma (p < .05). Using MDR, the authors detected significant gene-gene interactions with a best six-locus model among IL-4 -C33T, IL-13 R130Q, IL-4Ralpha I75V, IL-4Ralpha Q576R, STAT6 C2892T, and CD14 -C159T on the risk of asthma (OR = 4.43, 95% CI 1.30-15.04, p < .001, by 1000-fold permutation test).
CONCLUSIONS: These data suggest that genetic variants in the IL-13 gene may play an important role in the development of pediatric asthma in Middle China. In addition, the significant gene-gene interactions among IL-4 -C33T, IL-13 R130Q, IL-4Ralpha I75V, IL-4Ralpha Q576R, STAT6 C2892T, and CD14 -C159T may increase an individual’s susceptibility to asthma and contribute to the pathogenesis of asthma.
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哮喘气道平滑肌增厚与哮喘严重度相关，但与哮喘病程无关
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难治性哮喘的形态学和分子特征
