EQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS‐identified asthma genes. Issue 10 (24th July 2015)

• Record Type: Journal Article
• Authors: Li, X.; Hastie, A. T.; Hawkins, G. A.; Moore, W. C.; Ampleford, E. J.; Milosevic, J.; Li, H.; Busse, W. W.; Erzurum, S. C.; Kaminski, N.; Wenzel, S. E.; Meyers, D. A.; Bleecker, E. R.
• Is Part Of: Allergy. Volume 70:Issue 10(2015:Oct.)
• Page Start: 1309
• Page End: 1318
• Publication Date: 2015-07-24
• Subjects: Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.12683
• Languages: English
• ISSNs: 0105-4538

Abstract

<abstract abstract-type="main" id="all12683-abs-0001"> <title>Abstract</title> <sec id="all12683-sec-0001" sec-type="section"> <title>Background</title> <p>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.</p> </sec> <sec id="all12683-sec-0002" sec-type="section"> <title>Methods</title> <p> <italic>Cis</italic>‐eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, <italic> n</italic> = 107) and from bronchial alveolar lavage (BAL, <italic> n</italic> = 94).</p> </sec> <sec id="all12683-sec-0003" sec-type="section"> <title>Results</title> <p>For <italic>TSLP‐WDR36</italic> 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 <italic>TSLP</italic> in BAL (<italic>P </italic>=<italic> </italic>7.9 × 10<sup>−11</sup> and 5.4 × 10<sup>−4</sup>, respectively) and BEC, but not <italic>WDR36</italic>. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with <italic>TSLP</italic> expression levels. For <italic>ORMDL3‐GSDMB</italic> region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of <italic>GSDMB</italic> in BEC and BAL (<italic>P </italic>=<italic> </italic>1.3 × 10<sup>−4</sup> and 0.04) but not <italic>ORMDL3</italic>. rs992969 in the promoter region of <italic>IL33</italic> (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of <italic>IL33</italic> in BEC (<italic>P </italic>=<italic> </italic>1.3 × 10<sup>−6</sup>) but not in BAL.</p> </sec> <sec id="all12683-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Our study illustrates cell‐type‐specific regulation of the expression of asthma‐related genes documenting SNPs in <italic>TSLP</italic>, <italic> GSDMB</italic>, <italic> IL33</italic>, <italic> HLA‐DQB1</italic>, <italic> C11orf30</italic>, <italic> DEXI</italic>, <italic> CDHR3</italic>, and <italic>ZBTB10</italic> affect asthma risk through <italic>cis</italic>‐regulation of its gene expression. Whenever possible, disease‐relevant tissues should be used for transcription analysis. SNPs in <italic>TSLP</italic> may affect asthma risk through up‐regulating <italic>TSLP</italic> mRNA expression or protein secretion. Further functional studies are warranted.</p> </sec> </abstract>