Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, University of Maribor, Slomškov trg 15, 2000, Maribor, Slovenia.
Immunogenetics. 2014 Mar;66(3):143-51. doi: 10.1007/s00251-013-0755-0. Epub 2014 Jan 10.
Recent genome-wide association studies (GWAs) have identified several new genetic risk factors for asthma; however, their influence on disease behavior and treatment response is still unclear. The aim of our study was the association analysis of the most significant single nucleotide polymorphisms (SNPs) recently reported by GWAs in different phenotypes of childhood asthma and analysis of correlation between these SNPs and clinical parameters. We have genotyped 288 children with asthma and 276 healthy controls. We provided here first replication of bivariate associations between CA10 (p = 0.001) and SGK493 (p = 0.011) with asthma. In addition, we have identified new correlation between SNPs in CA10, SGK493, and CTNNA3 with asthma behavior and glucocorticoid treatment response. Asthma patients who carried G allele in SNP rs967676 in gene CA10 were associated with more pronounced airway obstruction, higher bronchial hyper-reactivity, and increased inflammation. Higher bronchial hyper-reactivity was also associated with C allele in SNP rs1440095 in gene SGK493 but only in nonatopic asthmatics. In addition, we found that patients who carried at least one T allele in SNP rs1786929 in CTNNA3 (p = 0.022) and atopic patients who carried at least one G allele in SNP rs967676 in gene CA10 (p = 0.034) had higher increase in pulmonary function after glucocorticoid therapy. Our results suggest genetic heterogeneity between atopic and nonatopic asthma. We provided further evidence that treatment response in childhood asthma is genetically predisposed, and we report here two novel SNPs in genes CA10 and CTNNA3 as potential pharmacogenetic biomarkers that could be used in personalized treatment in childhood asthma.
最近的全基因组关联研究（GWAS）已经确定了几个新的哮喘遗传风险因素；然而，它们对疾病行为和治疗反应的影响仍不清楚。我们的研究目的是分析最近 GWAS 报道的与儿童哮喘不同表型相关的最显著单核苷酸多态性（SNP）的关联分析，并分析这些 SNP 与临床参数之间的相关性。我们对 288 名哮喘儿童和 276 名健康对照进行了基因分型。我们首次复制了 CA10（p=0.001）和 SGK493（p=0.011）与哮喘的双变量关联。此外，我们还发现 CA10、SGK493 和 CTNNA3 中的 SNP 与哮喘行为和糖皮质激素治疗反应之间存在新的相关性。携带 CA10 基因中 SNP rs967676 G 等位基因的哮喘患者与更明显的气道阻塞、更高的支气管高反应性和炎症增加有关。SGK493 基因中 SNP rs1440095 的 C 等位基因也与非过敏性哮喘患者的高支气管高反应性有关。此外，我们发现 CTNNA3 基因中 SNP rs1786929 携带至少一个 T 等位基因的患者（p=0.022）和 CA10 基因中 SNP rs967676 携带至少一个 G 等位基因的过敏性哮喘患者（p=0.034）在糖皮质激素治疗后肺功能有更高的改善。我们的结果表明，过敏性和非过敏性哮喘之间存在遗传异质性。我们进一步证明，儿童哮喘的治疗反应具有遗传倾向，我们在这里报告了 CA10 和 CTNNA3 基因中的两个新的 SNP，它们可能成为儿童哮喘个体化治疗的潜在药效遗传学生物标志物。
