eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.
eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.
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支气管上皮细胞和支气管肺泡灌洗剂GWAS鉴定的哮喘基因的EQTL。
DOI：
10.1111/all.12683
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发表时间：
2015-10
期刊：
影响因子：
12.4
通讯作者：
Bleecker ER
中科院分区：
文献类型：
--
作者：
Li X;Hastie AT;Hawkins GA;Moore WC;Ampleford EJ;Milosevic J;Li H;Busse WW;Erzurum SC;Kaminski N;Wenzel SE;Meyers DA;Bleecker ER
全基因组关联研究（GWASs）已经确定了与哮喘相关的各种基因，然而，致病基因或单核苷酸多态性（SNP）仍然难以捉摸。我们试图通过结合表达数量性状位点（eQTL）和GWAS来剖析哮喘的功能基因/SNP。在来自人支气管上皮活检（BEC，n =107）和支气管肺泡灌洗（BAL，n = 94）的细胞中进行34个哮喘基因的顺式eQTL分析。对于TSLP-WDR 36区域，rs3806932（G等位基因，对嗜酸性粒细胞性食管炎有保护作用）和rs 2416257（A等位基因，与较低的嗜酸性粒细胞计数和对哮喘有保护作用）与BAL（P值分别为7.9x10−11和5.4x10−4）和BEC中TSLP表达降低相关，但与WDR 36无关。令人惊讶的是，rs 1837253（始终与哮喘相关）与TSLP表达水平无关。对于ORMDL 3-GSDMB区域，rs 8067378（G等位基因可预防哮喘）与BEC和BAL中GSDMB表达减少相关（P = 1.3x10 - 4和0.04），但与ORMDL 3无关。IL 33启动子区域的rs 992969（与嗜酸性粒细胞计数和哮喘风险相关的等位基因）与BEC中IL 33表达增加相关（P = 1.3x10−6），但与BAL中的IL 33表达无关。我们的研究说明了哮喘相关基因表达的细胞类型特异性调节，记录了TSLP、GSDMB、IL 33、HLA-DQB 1、C11 orf 30、DEXI、CDHR 3和ZBTB 10中的SNP通过顺式调节其基因表达影响哮喘风险。只要有可能，应使用疾病相关组织进行转录分析。TSLP中的SNPs可能通过上调TSLP mRNA表达或蛋白分泌而影响哮喘风险。进一步的功能研究是必要的。
Genome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs. Cis-eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n =107) and from bronchial alveolar lavage (BAL, n = 94). For TSLP-WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9x10−11 and 5.4x10−4, respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3-GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3x10−4 and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3x10−6) but not in BAL. Our study illustrates cell-type-specific regulation of the expression of asthma-related genes documenting SNPs in TSLP, GSDMB, IL33, HLA-DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis-regulation of its gene expression. Whenever possible, disease-relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up-regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted.