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

被引：84

作者：

Li, X. ^{[1
]}

Hastie, A. T. ^{[1
]}

Hawkins, G. A. ^{[1
]}

Moore, W. C. ^{[1
]}

Ampleford, E. J. ^{[1
]}

Milosevic, J. ^{[2
]}

Li, H. ^{[1
]}

Busse, W. W. ^{[3
]}

Erzurum, S. C. ^{[4
]}

Kaminski, N. ^{[5
]}

Wenzel, S. E. ^{[2
]}

Meyers, D. A. ^{[1
]}

Bleecker, E. R. ^{[1
]}

机构：

[1] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA

[2] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA

[3] Univ Wisconsin, Dept Med, Madison, WI USA

[4] Lerner Res Inst, Dept Pathobiol, Cleveland, OH USA

[5] Yale Univ, Sch Med, Pulm Crit Care & Sleep Med, New Haven, CT USA

来源：

ALLERGY | 2015年 / 70卷 / 10期

关键词：

asthma susceptibility genes; bronchial alveolar lavage; bronchial epithelial cells; eQTL; Genome-wide association studies; GENOME-WIDE ASSOCIATION; EXPRESSION; VARIANTS; RISK; LOCI;

D O I：

10.1111/all.12683

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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 x 10(-11) and 5.4 x 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 x 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 x 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.

引用

页码：1309 / 1318

页数：10

共 35 条

[1] A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations [J].

Bonnelykke, Klaus ;

Sleiman, Patrick ;

Nielsen, Kasper ;

Kreiner-Moller, Eskil ;

Mercader, Josep M. ;

Belgrave, Danielle ;

den Dekker, Herman T. ;

Husby, Anders ;

Sevelsted, Astrid ;

Faura-Tellez, Grissel ;

Mortensen, Li Juel ;

Paternoster, Lavinia ;

Flaaten, Richard ;

Molgaard, Anne ;

Smart, David E. ;

Thomsen, Philip F. ;

Rasmussen, Morten A. ;

Bonas-Guarch, Silvia ;

Holst, Claus ;

Nohr, Ellen A. ;

Yadav, Rachita ;

March, Michael E. ;

Blicher, Thomas ;

Lackie, Peter M. ;

Jaddoe, Vincent W. V. ;

Simpson, Angela ;

Holloway, John W. ;

Duijts, Liesbeth ;

Custovic, Adnan ;

Davies, Donna E. ;

Torrents, David ;

Gupta, Ramneek ;

Hollegaard, Mads V. ;

Hougaard, David M. ;

Hakonarson, Hakon ;

Bisgaard, Hans .

NATURE GENETICS, 2014, 46 (01) :51-+

[2] Gene expression profiles reveal molecular mechanisms involved in the progression and resolution of bleomycin-induced lung fibrosis [J].

Cabrera, Sandra ;

Selman, Moises ;

Lonzano-Bolanos, Alfredo ;

Konishi, Kazuhisa ;

Richards, Thomas J. ;

Kaminski, Naftali ;

Pardo, Annie .

AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2013, 304 (09) :L593-L601

[3] Rhinovirus Wheezing Illness and Genetic Risk of Childhood-Onset Asthma [J].

Caliskan, Minal ;

Bochkov, Yury A. ;

Kreiner-Moller, Eskil ;

Bonnelykke, Klaus ;

Stein, Michelle M. ;

Du, Gaixin ;

Bisgaard, Hans ;

Jackson, Daniel J. ;

Gern, James E. ;

Lemanske, Robert F., Jr. ;

Nicolae, Dan L. ;

Ober, Carole .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 368 (15) :1398-1407

[4] Common Regulatory Variation Impacts Gene Expression in a Cell Type-Dependent Manner [J].

Dimas, Antigone S. ;

Deutsch, Samuel ;

Stranger, Barbara E. ;

Montgomery, Stephen B. ;

Borel, Christelle ;

Attar-Cohen, Homa ;

Ingle, Catherine ;

Beazley, Claude ;

Arcelus, Maria Gutierrez ;

Sekowska, Magdalena ;

Gagnebin, Marilyne ;

Nisbett, James ;

Deloukas, Panos ;

Dermitzakis, Emmanouil T. ;

Antonarakis, Stylianos E. .

SCIENCE, 2009, 325 (5945) :1246-1250

[5] Gene Expression in Skin and Lymphoblastoid Cells: Refined Statistical Method Reveals Extensive Overlap in cis-eQTL Signals [J].

Ding, Jun ;

Gudjonsson, Johann E. ;

Liang, Liming ;

Stuart, Philip E. ;

Li, Yun ;

Chen, Wei ;

Weichenthal, Michael ;

Ellinghaus, Eva ;

Franke, Andre ;

Cookson, William ;

Nair, Rajan P. ;

Elder, James T. ;

Abecasis, Goncalo R. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2010, 87 (06) :779-789

[6] A genome-wide association study of global gene expression [J].

Dixon, Anna L. ;

Liang, Liming ;

Moffatt, Miriam F. ;

Chen, Wei ;

Heath, Simon ;

Wong, Kenny C. C. ;

Taylor, Jenny ;

Burnett, Edward ;

Gut, Ivo ;

Farrall, Martin ;

Lathrop, G. Mark ;

Abecasis, Goncalo R. ;

Cookson, William O. C. .

NATURE GENETICS, 2007, 39 (10) :1202-1207

[7] Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype [J].

Ferreira, Manuel A. R. ;

Matheson, Melanie C. ;

Tang, Clara S. ;

Granell, Raquel ;

Ang, Wei ;

Hui, Jennie ;

Kiefer, Amy K. ;

Duffy, David L. ;

Baltic, Svetlana ;

Danoy, Patrick ;

Bui, Minh ;

Price, Loren ;

Sly, Peter D. ;

Eriksson, Nicholas ;

Madden, Pamela A. ;

Abramson, Michael J. ;

Holt, Patrick G. ;

Heath, Andrew C. ;

Hunter, Michael ;

Musk, Bill ;

Robertson, Colin F. ;

Le Souef, Peter ;

Montgomery, Grant W. ;

Henderson, A. John ;

Tung, Joyce Y. ;

Dharmage, Shyamali C. ;

Brown, Matthew A. ;

James, Alan ;

Thompson, Philip J. ;

Pennell, Craig ;

Martin, Nicholas G. ;

Evans, David M. ;

Hinds, David A. ;

Hopper, John L. .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2014, 133 (06) :1564-1571

[8] Identification of IL6R and chromosome 11q13.5 as risk loci for asthma [J].

Ferreira, Manuel A. R. ;

Matheson, Melanie C. ;

Duffy, David L. ;

Marks, Guy B. ;

Hui, Jennie ;

Le Souef, Peter ;

Danoy, Patrick ;

Baltic, Svetlana ;

Nyholt, Dale R. ;

Jenkins, Mark ;

Hayden, Catherine ;

Willemsen, Gonneke ;

Ang, Wei ;

Kuokkanen, Mikko ;

Beilby, John ;

Cheah, Faang ;

de Geus, Eco J. C. ;

Ramasamy, Adaikalavan ;

Vedantam, Sailaja ;

Salomaa, Veikko ;

Madden, Pamela A. ;

Heath, Andrew C. ;

Hopper, John L. ;

Visscher, Peter M. ;

Musk, Bill ;

Leeder, Stephen R. ;

Jarvelin, Marjo-Riitta ;

Pennell, Craig ;

Boomsma, Dorret I. ;

Hirschhorn, Joel N. ;

Walters, Haydn ;

Martin, Nicholas G. ;

James, Alan ;

Jones, Graham ;

Abramson, Michael J. ;

Robertson, Colin F. ;

Dharmage, Shyamali C. ;

Brown, Matthew A. ;

Montgomery, Grant W. ;

Thompson, Philip J. .

LANCET, 2011, 378 (9795) :1006-1014

[9] Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression [J].

Fu, Jingyuan ;

Wolfs, Marcel G. M. ;

Deelen, Patrick ;

Westra, Harm-Jan ;

Fehrmann, Rudolf S. N. ;

Meerman, Gerard J. Te ;

Buurman, Wim A. ;

Rensen, Sander S. M. ;

Groen, Harry J. M. ;

Weersma, Rinse K. ;

van den Berg, Leonard H. ;

Veldink, Jan ;

Ophoff, Roel A. ;

Snieder, Harold ;

van Heel, David ;

Jansen, Ritsert C. ;

Hofker, Marten H. ;

Wijmenga, Cisca ;

Franke, Lude .

PLOS GENETICS, 2012, 8 (01)

[10] Decoding asthma: Translating genetic variation in IL33 and IL1RL1 into disease pathophysiology [J].

Grotenboer, Neomi S. ;

Ketelaar, Maria E. ;

Koppelman, Gerard H. ;

Nawijn, Martijn C. .

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2013, 131 (03) :856-+

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