BACKGROUND: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.
METHODS: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).
RESULTS: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 = 7.9 × 10(-11) and 5.4 × 10(-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 = 1.3 × 10(-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 = 1.3 × 10(-6) ) but not in BAL.
CONCLUSIONS: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.
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【eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.].
【支气管上皮细胞的eQTL和支气管肺泡灌洗解密了GWAS鉴定的哮喘基因。】
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DOI：10.1111/all.12683文章类型：杂志文章
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背景：全基因组关联研究（GWAS）已鉴定出与哮喘相关的各种基因，但因果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定量性状基因座（eQTL）和GWASs来分析哮喘的功能基因/ SNP。
方法：对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34种哮喘基因进行Cis-eQTL分析。
结果：对于TSLP-WDR36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rs2416257（等位基因与嗜酸性粒细胞减少和哮喘相关）与BAL中TSLP的表达降低相关（P = 7.9×10（-11） ）和5.4×10（-4））和BEC，但不包括WDR36。出乎意料的是，rs1837253（与哮喘相关）始终与TSLP表达水平无关。对于ORMDL3-GSDMB区，rs8067378（对哮喘具有保护作用的G等位基因）与BEC和BAL中GSDMB的表达降低相关（P = 1.3×10（-4）和0.04），而与ORMDL3无关。 IL33（与较高的嗜酸性粒细胞计数和哮喘风险有关的等位基因）启动子区域中的rs992969与BEC中IL33表达的增加相关（P = 1.3×10（-6）），但与BAL中的IL33表达无关。
结论：我们的研究阐明了哮喘相关基因表达的细胞类型特异性调控，该基因表达TSLP，GSDMB，IL33，HLA-DQB1，C11orf30，DEXI，CDHR3和ZBTB10中的SNPs，通过顺式调控其基因影响哮喘风险表达。只要有可能，应使用与疾病相关的组织进行转录分析。 TSLP中的SNP可能通过上调TSLP mRNA表达或蛋白质分泌来影响哮喘风险。有必要进行进一步的功能研究。
方法：对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34种哮喘基因进行Cis-eQTL分析。
结果：对于TSLP-WDR36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rs2416257（等位基因与嗜酸性粒细胞减少和哮喘相关）与BAL中TSLP的表达降低相关（P = 7.9×10（-11） ）和5.4×10（-4））和BEC，但不包括WDR36。出乎意料的是，rs1837253（与哮喘相关）始终与TSLP表达水平无关。对于ORMDL3-GSDMB区，rs8067378（对哮喘具有保护作用的G等位基因）与BEC和BAL中GSDMB的表达降低相关（P = 1.3×10（-4）和0.04），而与ORMDL3无关。 IL33（与较高的嗜酸性粒细胞计数和哮喘风险有关的等位基因）启动子区域中的rs992969与BEC中IL33表达的增加相关（P = 1.3×10（-6）），但与BAL中的IL33表达无关。
结论：我们的研究阐明了哮喘相关基因表达的细胞类型特异性调控，该基因表达TSLP，GSDMB，IL33，HLA-DQB1，C11orf30，DEXI，CDHR3和ZBTB10中的SNPs，通过顺式调控其基因影响哮喘风险表达。只要有可能，应使用与疾病相关的组织进行转录分析。 TSLP中的SNP可能通过上调TSLP mRNA表达或蛋白质分泌来影响哮喘风险。有必要进行进一步的功能研究。
