Institute of Epidemiology, Ulm University, Ulm, Germany.
Clin Exp Allergy. 2009 Dec;39(12):1875-88. doi: 10.1111/j.1365-2222.2009.03364.x.
Common polymorphisms have been identified in genes suspected to play a role in asthma. We investigated their associations with wheeze and allergy in a case-control sample from Phase 2 of the International Study of Asthma and Allergies in Childhood.
We compared 1105 wheezing and 3137 non-wheezing children aged 8-12 years from 17 study centres in 13 countries. Genotyping of 55 candidate single nucleotide polymorphisms (SNPs) in 14 genes was performed using the Sequenom System. Logistic regression models were fitted separately for each centre and each SNP. A combined per allele odds ratio and measures of heterogeneity between centres were derived by random effects meta-analysis.
Significant associations with wheeze in the past year were detected in only four genes (IL4R, TLR4, MS4A2, TLR9, P<0.05), with per allele odds ratios generally <1.3. Variants in IL4R and TLR4 were also related to allergen-specific IgE, while polymorphisms in FCER1B (MS4A2) and TLR9 were not. There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE. Heterogeneity of effects across centres was rare, despite differences in allele frequencies.
Despite the biological plausibility of IgE-related mechanisms in asthma, very few of the tested candidates showed evidence of association with both wheeze and increased IgE levels. We were unable to confirm associations of the positional candidates DPP10 and PHF11 with wheeze, although our study had ample power to detect the expected associations of IL13 variants with IgE and SPINK5 variants with eczema.
已经鉴定出一些常见的基因多态性，这些基因被怀疑在哮喘中发挥作用。我们在儿童哮喘和过敏国际研究的第二阶段的病例对照样本中调查了这些多态性与喘息和过敏的关联。
我们比较了来自 13 个国家 17 个研究中心的 1105 名喘息和 3137 名非喘息 8-12 岁儿童。使用 Sequenom 系统对 14 个基因中的 55 个候选单核苷酸多态性（SNP）进行基因分型。为每个中心和每个 SNP 单独拟合逻辑回归模型。通过随机效应荟萃分析得出每个等位基因的优势比和中心之间异质性的测量值。
仅在四个基因（IL4R、TLR4、MS4A2、TLR9）中检测到与过去一年喘息相关的显著关联（P<0.05），每个等位基因的优势比通常<1.3。IL4R 和 TLR4 中的变体也与过敏原特异性 IgE 相关，而 FCER1B（MS4A2）和 TLR9 中的变体则不然。SPINK5 变体与可见湿疹（而非 IgE 水平）之间以及 IL13 变体与总 IgE 之间也存在高度显著的关联（P<0.001）。尽管等位基因频率存在差异，但中心之间的效应异质性很少。
尽管 IgE 相关机制在哮喘中具有生物学合理性，但在测试的候选者中，很少有证据表明与喘息和 IgE 水平升高有关。我们无法证实 DPP10 和 PHF11 位置候选物与喘息之间的关联，尽管我们的研究有足够的能力检测到预期的 IL13 变体与 IgE 和 SPINK5 变体与湿疹的关联。
