Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany; Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
J Allergy Clin Immunol. 2015 Oct;136(4):893-903.e14. doi: 10.1016/j.jaci.2015.03.014. Epub 2015 Apr 28.
Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies.
We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility.
We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo.
Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 × 10(-5) and P = .0035, respectively) and case-control (P = 3.15 × 10(-8) and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression.
Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.
染色体 17q21 上的粘蛋白 1 样 3（ORMDL3）基因与全基因组关联研究中的儿童哮喘一直密切相关。
我们研究了 ORMDL3 及其周围的遗传变异，这些变异可以改变 ORMDL3 的功能，从而导致哮喘易感性。
我们在一个横断面（国际儿童哮喘与过敏研究第二期，共 3557 名受试者，281 名哮喘患者）和病例对照（多中心儿童哮喘遗传学研究/国际儿童哮喘与过敏研究第二期，共 1446 名受试者，763 名哮喘患者）数据集进行了 ORMDL3 基因座的单体型分析和精细定位，以确定该基因座中潜在的因果单核苷酸多态性（SNP）。对与哮喘相关的最显著多态性进行了体外转录因子结合和启动子活性分析以及体外刺激后 PBMC 基因表达分析。
两个单体型（H1 和 H2）在横断面（P = 9.9×10(-5)和 P =.0035，分别）和病例对照（P = 3.15×10(-8)和 P =.0021，分别）人群中与哮喘显著相关。鉴定出 rs8076131 和 rs4065275 多态性驱动这些效应。对于 rs4065275，发现转录因子结合的定量差异，而对于 rs8076131，通过使用不同的细胞系和 PBMC，观察到上游刺激因子 1 和 2 转录因子结合的变化。这可能导致体外检测到的荧光素酶活性的变化与 ORMDL3 基因表达以及 IL-4 和 IL-13 细胞因子水平的变化相平行，这些变化以等位基因特异性的方式响应先天和适应性刺激。这两个 SNP 与先前与 ORMDL3 基因表达改变相关的 17q21 哮喘相关 SNP 高度连锁不平衡。
ORMDL3 假定启动子区域的多态性与儿童哮喘相关，改变了 ORMDL3 的转录调控，与 TH2 细胞因子水平的变化相关，因此可能导致 17q21 上的儿童哮喘易感性信号。
