X Li1, A T Hastie1, G A Hawkins1, W C Moore1, E J Ampleford1, J Milosevic2, H Li1, W W Busse3, S C Erzurum4, N Kaminski5, S E Wenzel2, D A Meyers1, E R Bleecker1. 1. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA. 2. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. 3. Department of Medicine, University of Wisconsin, Madison, WI, USA. 4. Department of Pathobiology, The Lerner Research Institute, Cleveland, OH, USA. 5. Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA.
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.
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.
Authors: Anna L Dixon; Liming Liang; Miriam F Moffatt; Wei Chen; Simon Heath; Kenny C C Wong; Jenny Taylor; Edward Burnett; Ivo Gut; Martin Farrall; G Mark Lathrop; Gonçalo R Abecasis; William O C Cookson Journal: Nat Genet Date: 2007-09-16 Impact factor: 38.330
Authors: Lucia A Hindorff; Praveen Sethupathy; Heather A Junkins; Erin M Ramos; Jayashri P Mehta; Francis S Collins; Teri A Manolio Journal: Proc Natl Acad Sci U S A Date: 2009-05-27 Impact factor: 11.205
Authors: Néomi S Grotenboer; Maria E Ketelaar; Gerard H Koppelman; Martijn C Nawijn Journal: J Allergy Clin Immunol Date: 2013-02-04 Impact factor: 10.793
Authors: Patrick M A Sleiman; James Flory; Marcin Imielinski; Jonathan P Bradfield; Kiran Annaiah; Saffron A G Willis-Owen; Kai Wang; Nicholas M Rafaels; Sven Michel; Klaus Bonnelykke; Haitao Zhang; Cecilia E Kim; Edward C Frackelton; Joseph T Glessner; Cuiping Hou; F George Otieno; Erin Santa; Kelly Thomas; Ryan M Smith; Wendy R Glaberson; Maria Garris; Rosetta M Chiavacci; Terri H Beaty; Ingo Ruczinski; Jordan S Orange; Jordan M Orange; Julian Allen; Jonathan M Spergel; Robert Grundmeier; Rasika A Mathias; Jason D Christie; Erika von Mutius; William O C Cookson; Michael Kabesch; Miriam F Moffatt; Michael M Grunstein; Kathleen C Barnes; Marcella Devoto; Mark Magnusson; Hongzhe Li; Struan F A Grant; Hans Bisgaard; Hakon Hakonarson Journal: N Engl J Med Date: 2009-12-23 Impact factor: 91.245
Authors: Dara G Torgerson; Elizabeth J Ampleford; Grace Y Chiu; W James Gauderman; Christopher R Gignoux; Penelope E Graves; Blanca E Himes; Albert M Levin; Rasika A Mathias; Dana B Hancock; James W Baurley; Celeste Eng; Debra A Stern; Juan C Celedón; Nicholas Rafaels; Daniel Capurso; David V Conti; Lindsey A Roth; Manuel Soto-Quiros; Alkis Togias; Xingnan Li; Rachel A Myers; Isabelle Romieu; David J Van Den Berg; Donglei Hu; Nadia N Hansel; Ryan D Hernandez; Elliott Israel; Muhammad T Salam; Joshua Galanter; Pedro C Avila; Lydiana Avila; Jose R Rodriquez-Santana; Rocio Chapela; William Rodriguez-Cintron; Gregory B Diette; N Franklin Adkinson; Rebekah A Abel; Kevin D Ross; Min Shi; Mezbah U Faruque; Georgia M Dunston; Harold R Watson; Vito J Mantese; Serpil C Ezurum; Liming Liang; Ingo Ruczinski; Jean G Ford; Scott Huntsman; Kian Fan Chung; Hita Vora; Xia Li; William J Calhoun; Mario Castro; Juan J Sienra-Monge; Blanca del Rio-Navarro; Klaus A Deichmann; Andrea Heinzmann; Sally E Wenzel; William W Busse; James E Gern; Robert F Lemanske; Terri H Beaty; Eugene R Bleecker; Benjamin A Raby; Deborah A Meyers; Stephanie J London; Frank D Gilliland; Esteban G Burchard; Fernando D Martinez; Scott T Weiss; L Keoki Williams; Kathleen C Barnes; Carole Ober; Dan L Nicolae Journal: Nat Genet Date: 2011-07-31 Impact factor: 38.330
Authors: Barbara E Stranger; Stephen B Montgomery; Antigone S Dimas; Leopold Parts; Oliver Stegle; Catherine E Ingle; Magda Sekowska; George Davey Smith; David Evans; Maria Gutierrez-Arcelus; Alkes Price; Towfique Raj; James Nisbett; Alexandra C Nica; Claude Beazley; Richard Durbin; Panos Deloukas; Emmanouil T Dermitzakis Journal: PLoS Genet Date: 2012-04-19 Impact factor: 5.917
Authors: Wei Wu; Nilesh Dave; George C Tseng; Thomas Richards; Eric P Xing; Naftali Kaminski Journal: BMC Bioinformatics Date: 2005-12-28 Impact factor: 3.169
Authors: Miriam F Moffatt; Michael Kabesch; Liming Liang; Anna L Dixon; David Strachan; Simon Heath; Martin Depner; Andrea von Berg; Albrecht Bufe; Ernst Rietschel; Andrea Heinzmann; Burkard Simma; Thomas Frischer; Saffron A G Willis-Owen; Kenny C C Wong; Thomas Illig; Christian Vogelberg; Stephan K Weiland; Erika von Mutius; Gonçalo R Abecasis; Martin Farrall; Ivo G Gut; G Mark Lathrop; William O C Cookson Journal: Nature Date: 2007-07-04 Impact factor: 49.962
Authors: Xingnan Li; Gregory A Hawkins; Wendy C Moore; Annette T Hastie; Elizabeth J Ampleford; Jadranka Milosevic; Huashi Li; William W Busse; Serpil C Erzurum; Naftali Kaminski; Sally E Wenzel; Eugene R Bleecker; Deborah A Meyers Journal: J Asthma Date: 2016-04-06 Impact factor: 2.515
Authors: Brian D Modena; Eugene R Bleecker; William W Busse; Serpil C Erzurum; Benjamin M Gaston; Nizar N Jarjour; Deborah A Meyers; Jadranka Milosevic; John R Tedrow; Wei Wu; Naftali Kaminski; Sally E Wenzel Journal: Am J Respir Crit Care Med Date: 2017-06-01 Impact factor: 21.405
Authors: Jennie G Ono; Benjamin I Kim; Yize Zhao; Paul J Christos; Yohannes Tesfaigzi; Tilla S Worgall; Stefan Worgall Journal: J Clin Invest Date: 2020-02-03 Impact factor: 14.808
Authors: Jessie Nicodemus-Johnson; Rachel A Myers; Noburu J Sakabe; Debora R Sobreira; Douglas K Hogarth; Edward T Naureckas; Anne I Sperling; Julian Solway; Steven R White; Marcelo A Nobrega; Dan L Nicolae; Yoav Gilad; Carole Ober Journal: JCI Insight Date: 2016-12-08
Authors: John P Reilly; Fan Wang; Tiffanie K Jones; Jessica A Palakshappa; Brian J Anderson; Michael G S Shashaty; Thomas G Dunn; Erik D Johansson; Thomas R Riley; Brian Lim; Jason Abbott; Caroline A G Ittner; Edward Cantu; Xihong Lin; Carmen Mikacenic; Mark M Wurfel; David C Christiani; Carolyn S Calfee; Michael A Matthay; Jason D Christie; Rui Feng; Nuala J Meyer Journal: Intensive Care Med Date: 2018-10-21 Impact factor: 17.440
Authors: Kim Valette; Zhonglin Li; Valentin Bon-Baret; Arnaud Chignon; Jean-Christophe Bérubé; Aida Eslami; Jennifer Lamothe; Nathalie Gaudreault; Philippe Joubert; Ma'en Obeidat; Maarten van den Berge; Wim Timens; Don D Sin; David C Nickle; Ke Hao; Catherine Labbé; Krystelle Godbout; Andréanne Côté; Michel Laviolette; Louis-Philippe Boulet; Patrick Mathieu; Sébastien Thériault; Yohan Bossé Journal: Commun Biol Date: 2021-06-08