Research Unit, Hospital Universitario N.S. de Candelaria, Universidad de La Laguna, Santa Cruz de Tenerife, Spain.
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Clin Exp Allergy. 2017 May;47(5):618-626. doi: 10.1111/cea.12883. Epub 2017 Feb 5.
Genetic susceptibility to asthma is currently linked to a handful of genes which have a limited ability to predict the overall disease risk, suggesting the existence of many other genes involved in disease development. Accumulated evidence from association studies in genes related by biological pathways could reveal novel asthma genes.
To reveal novel asthma susceptibility genes by means of a pathway-based association study.
Based on summary data from a previous a genomewide association study (GWAS) of asthma, we first identified significant biological pathways using a gene-set enrichment analysis. We then mapped all tested single nucleotide polymorphisms (SNPs) on the genes contributing to significant pathways and prioritized those with a disproportionate number of nominal significant associations for further studies. For those prioritized genes, association studies were performed for selected SNPs in independent case-control samples (n = 1765) using logistic regression models, and results were meta-analysed with those from the GWAS.
Two biological processes were significantly enriched: the cytokine-cytokine receptor interaction (P = 0.002) and the Wnt signalling (P = 0.012). From the 417 genes interacting in these two pathways, 10 showed an excess of nominal associations, including a known asthma susceptibility locus (encoding SMAD family member 3) and other novel candidate genes. From the latter, association studies of 14 selected SNPs evidenced replication in a locus near the frizzled class receptor 6 (FZD6) gene (P = 9.90 × 10 ), which had a consistent direction of effects with the GWAS findings (meta-analysed odds ratio = 1.49; P = 5.87 × 10 ) and was in high linkage disequilibrium with expression quantitative trait loci in lung tissues.
This study revealed the importance of two biological pathways in asthma pathogenesis and identified a novel susceptibility locus near Wnt signalling genes.
目前，哮喘的遗传易感性与少数几个基因有关，这些基因只能有限地预测疾病的总体风险，这表明有许多其他基因参与了疾病的发展。通过对生物学途径相关基因的关联研究积累的证据可能会揭示新的哮喘基因。
通过基于途径的关联研究揭示新的哮喘易感基因。
根据先前哮喘全基因组关联研究（GWAS）的汇总数据，我们首先使用基因集富集分析来确定显著的生物学途径。然后，我们将所有测试的单核苷酸多态性（SNP）映射到参与显著途径的基因上，并优先考虑那些具有不成比例数量的名义显著关联的基因，以便进一步研究。对于那些优先考虑的基因，我们使用逻辑回归模型在独立病例对照样本（n=1765）中对选定的 SNP 进行了关联研究，并与 GWAS 的结果进行了荟萃分析。
两个生物过程显著富集：细胞因子-细胞因子受体相互作用（P=0.002）和 Wnt 信号（P=0.012）。在这两种途径相互作用的 417 个基因中，有 10 个表现出过多的名义关联，包括一个已知的哮喘易感基因座（编码 SMAD 家族成员 3）和其他新的候选基因。在后者中，14 个选定 SNP 的关联研究在 frizzled 类受体 6（FZD6）基因附近的一个基因座中得到了证实（P=9.90×10-9），其与 GWAS 结果的效应方向一致（荟萃分析的比值比=1.49；P=5.87×10-8），并且与肺组织中的表达数量性状基因座高度连锁不平衡。
本研究揭示了两个生物学途径在哮喘发病机制中的重要性，并在 Wnt 信号基因附近发现了一个新的易感基因座。
