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. 2015 Oct;70(10):1309-18.
doi: 10.1111/all.12683. Epub 2015 Jul 24.

eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes

X Li  1 , A T Hastie  1 , G A Hawkins  1 , W C Moore  1 , E J Ampleford  1 , J Milosevic  2 , H Li  1 , W W Busse  3 , S C Erzurum  4 , N Kaminski  5 , S E Wenzel  2 , D A Meyers  1 , E R Bleecker  1
Affiliations

eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes

X Li et al. Allergy. 2015 Oct.

Abstract

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.

Keywords: Genome-wide association studies; asthma susceptibility genes; bronchial alveolar lavage; bronchial epithelial cells; eQTL.

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Conflict of interest statement

Conflict of interest: W.W. Busse has received consultancy fees from Novartis, GlaxoSmithKline, Genentech, Pfizer and Roche; has received consultancy fees from Circassia for the Data Monitoring Board; has received consultancy fees from Boston Scientific for the Data Monitoring Board and consultancy fees from ICON for the Study Oversight Committee; has received research support from the NIH/NIAID and NIH/NHLBI; and receives royalties from Elsevier.

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