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eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS‐identified asthma genes
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| Zeitschriftentitel: | Allergy |
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| Personen und Körperschaften: | , , , , , , , , , , , , |
| In: | Allergy, 70, 2015, 10, S. 1309-1318 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Genome‐wide association studies (<jats:styled-content style="fixed-case">GWAS</jats:styled-content>s) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (<jats:styled-content style="fixed-case">SNP</jats:styled-content>s) remain elusive. We sought to dissect functional genes/<jats:styled-content style="fixed-case">SNP</jats:styled-content>s for asthma by combining expression quantitative trait loci (<jats:styled-content style="fixed-case">eQTL</jats:styled-content>s) and <jats:styled-content style="fixed-case">GWAS</jats:styled-content>s.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p><jats:italic>Cis</jats:italic>‐<jats:styled-content style="fixed-case">eQTL</jats:styled-content> analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (<jats:styled-content style="fixed-case">BEC</jats:styled-content>,<jats:italic> n</jats:italic> = 107) and from bronchial alveolar lavage (<jats:styled-content style="fixed-case">BAL</jats:styled-content>,<jats:italic> n</jats:italic> = 94).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>For <jats:italic><jats:styled-content style="fixed-case">TSLP</jats:styled-content>‐<jats:styled-content style="fixed-case">WDR</jats:styled-content>36</jats: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 <jats:italic><jats:styled-content style="fixed-case">TSLP</jats:styled-content></jats:italic> in <jats:styled-content style="fixed-case">BAL</jats:styled-content> (<jats:italic>P </jats:italic>=<jats:italic> </jats:italic>7.9 × 10<jats:sup>−11</jats:sup> and 5.4 × 10<jats:sup>−4</jats:sup>, respectively) and <jats:styled-content style="fixed-case">BEC</jats:styled-content>, but not <jats:italic><jats:styled-content style="fixed-case">WDR</jats:styled-content>36</jats:italic>. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with <jats:italic><jats:styled-content style="fixed-case">TSLP</jats:styled-content></jats:italic> expression levels. For <jats:italic><jats:styled-content style="fixed-case">ORMDL</jats:styled-content>3‐<jats:styled-content style="fixed-case">GSDMB</jats:styled-content></jats:italic> region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of <jats:italic><jats:styled-content style="fixed-case">GSDMB</jats:styled-content></jats:italic> in <jats:styled-content style="fixed-case">BEC</jats:styled-content> and <jats:styled-content style="fixed-case">BAL</jats:styled-content> (<jats:italic>P </jats:italic>=<jats:italic> </jats:italic>1.3 × 10<jats:sup>−4</jats:sup> and 0.04) but not <jats:italic><jats:styled-content style="fixed-case">ORMDL</jats:styled-content>3</jats:italic>. rs992969 in the promoter region of <jats:italic><jats:styled-content style="fixed-case">IL</jats:styled-content>33</jats:italic> (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of <jats:italic><jats:styled-content style="fixed-case">IL</jats:styled-content>33</jats:italic> in <jats:styled-content style="fixed-case">BEC</jats:styled-content> (<jats:italic>P </jats:italic>=<jats:italic> </jats:italic>1.3 × 10<jats:sup>−6</jats:sup>) but not in <jats:styled-content style="fixed-case">BAL</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our study illustrates cell‐type‐specific regulation of the expression of asthma‐related genes documenting <jats:styled-content style="fixed-case">SNP</jats:styled-content>s in <jats:italic><jats:styled-content style="fixed-case">TSLP</jats:styled-content></jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">GSDMB</jats:styled-content></jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">IL</jats:styled-content>33</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">HLA</jats:styled-content>‐<jats:styled-content style="fixed-case">DQB</jats:styled-content>1</jats:italic>,<jats:italic> C11orf30</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">DEXI</jats:styled-content></jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">CDHR</jats:styled-content>3</jats:italic>, and <jats:italic><jats:styled-content style="fixed-case">ZBTB</jats:styled-content>10</jats:italic> affect asthma risk through <jats:italic>cis</jats:italic>‐regulation of its gene expression. Whenever possible, disease‐relevant tissues should be used for transcription analysis. <jats:styled-content style="fixed-case">SNP</jats:styled-content>s in <jats:italic><jats:styled-content style="fixed-case">TSLP</jats:styled-content></jats:italic> may affect asthma risk through up‐regulating <jats:italic><jats:styled-content style="fixed-case">TSLP</jats:styled-content></jats:italic> <jats:styled-content style="fixed-case">mRNA</jats:styled-content> expression or protein secretion. Further functional studies are warranted.</jats:p></jats:sec> |
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| Umfang: | 1309-1318 |
| ISSN: |
0105-4538
1398-9995 |
| DOI: | 10.1111/all.12683 |