Novel childhood asthma genes interact with in utero and early-life tobacco smoke exposure

作者: Salome Scholtens , Dirkje S Postma , Miriam F Moffatt , Sviatlana Panasevich , Raquel Granell

DOI: 10.1016/J.JACI.2013.08.049

关键词: MedicineGeneticsCandidate geneTobacco smokePassive smokingMissing heritability problemSingle-nucleotide polymorphismImmunologyGenetic predispositionAsthmaMotile cilium

摘要: To the Editor: Complex diseases, including asthma, have genetic and environmental origins. Genome-wide association studies identified multiple genes for development of yet they only explain a limited proportion asthma heritability. Interactions between predisposition exposure to passive smoking might in part hidden heritability childhood asthma. However, date, this approach has not been reported discovery interactions tobacco smoke exposure. We performed genome-wide interaction study (GWIS) on identify that interact with 2 well-known risk factors childhood-onset asthma: utero exposure. We meta-analyzed results from 9 participating GABRIEL consortium1 more than 6,000 subjects European descent. replicated our findings 4 independent 13,000 subjects. Childhood-onset was defined as diagnosed by doctor before age 16 years, which is consistent definition consortium.1 In “exposure maternal at any time during pregnancy.” Childhood birth until years age.” Details number subjects, design individual studies, outcome definitions are provided Tables E1 E4 article's Online Repository www.jacionline.org. The effects were analyzed separately. All using logistic regression model containing effect, effect exposure, an term indicating Further methodological considerations GWISs details statistical analyses described www.jacionline.org. For meta-analysis consisted 2,654 cases 3,073 control derived 7 (see Table E1). Overall, increased Fig www.jacionline.org). A total 536,705 single nucleotide polymorphisms (SNPs) included meta-analysis. E2 www.jacionline.org shows Manhattan plot. 27 SNPs sample P value less 10−4 based fixed (Table I see E5 Findings did reach significance but over all included, no significant heterogeneity across present (P Q-statistic < .05). Four these chromosome 10 high linkage disequilibrium each other (r2 = 0.82-0.96). The most prominent marker located 18 near EPB41L3 (Forest plot, E3 E6 associations exposed nonexposed belongs protein 4.1 family membrane-associated proteins, involved cell-cell junctions,2 play role apoptosis.3 literature affects expression biological processes, such cell proliferation apoptosis, influences lung child general.4 Our data suggest potentially occur through mechanisms involving additional text Repository). Table I Results GWIS asthma For 3,048 3,509 538,233 35 model. excluded because showed heterogeneity, random greater 10−4. significance. II E7 www.jacionline.org) top SNPs. Seven 5 (except rs2312164) 0.83-1.00). Table II Results asthma The 6 PACRG (parkin coregulated gene; Forest E8 next overlapping promoter region parkin (PARK2).5 gene associated leprosy parkinsonian diseases important motile cilia function morphogenesis.2,6 relatively highly expressed trachea nasal mucosa. Ciliary dysfunction impair mucus clearance airways shown affect severity. changes ciliary particularly children smoke. The previously respect (ie, TNF,7 GSTP1,7 ADAM338) among hits. This can be explained fact variants candidate strong main development. Bouzigon et al9 pronounced 17q21 early-onset early-life those without. markers similar direction, significant. This first hypothesis-free specifically aiming disease found suggestive evidence rs8094633 rs1575472 general Interestingly, interacting different same pathway missing Future research needs confirm further unravel pathways.

参考文章(10)
Dimitra Dafou, Barbara Grun, John Sinclair, Kate Lawrenson, Elizabeth C. Benjamin, Estrid Hogdall, Susanne Kruger-Kjaer, Lise Christensen, Heidi M. Sowter, Ahmed Al-Attar, Richard Edmondson, Stephen Darby, Andrew Berchuck, Peter W. Laird, C. Leigh Pearce, Susan J. Ramus, Ian J. Jacobs, Simon A. Gayther, Microcell-mediated chromosome transfer identifies EPB41L3 as a functional suppressor of epithelial ovarian cancers. Neoplasia. ,vol. 12, pp. 579- 589 ,(2010) , 10.1593/NEO.10340
Gert S. Maritz, Richard Harding, Life-long Programming Implications of Exposure to Tobacco Smoking and Nicotine Before and Soon After Birth: Evidence for Altered Lung Development International Journal of Environmental Research and Public Health. ,vol. 8, pp. 875- 898 ,(2011) , 10.3390/IJERPH8030875
Andrew B West, Paul J Lockhart, Casey O'Farell, Matthew J Farrer, None, Identification of a novel gene linked to parkin via a bi-directional promoter. Journal of Molecular Biology. ,vol. 326, pp. 11- 19 ,(2003) , 10.1016/S0022-2836(02)01376-1
N. E. Reijmerink, M. Kerkhof, G. H. Koppelman, J. Gerritsen, J. C. de Jongste, H. A. Smit, B. Brunekreef, D. S. Postma, Smoke exposure interacts with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness. Allergy. ,vol. 64, pp. 898- 904 ,(2009) , 10.1111/J.1398-9995.2009.01939.X
S. Panasevich, C. Lindgren, J. Kere, M. Wickman, G. Pershagen, F. Nyberg, E. Melén, Interaction between early maternal smoking and variants in TNF and GSTP1 in childhood wheezing. Clinical & Experimental Allergy. ,vol. 40, pp. 458- 467 ,(2010) , 10.1111/J.1365-2222.2010.03452.X
PAUL J. LOCKHART, ANDREW B. WEST, CASEY A. O'FARRELL, MATTHEW J. FARRER, Identification of a Novel Gene Linked to Parkin via a Bidirectional Promoter Annals of the New York Academy of Sciences. ,vol. 991, pp. 311- 314 ,(2006) , 10.1111/J.1749-6632.2003.TB07493.X
Emmanuelle Bouzigon, Eve Corda, Hugues Aschard, Marie-Hélène Dizier, Anne Boland, Jean Bousquet, Nicolas Chateigner, Frédéric Gormand, Jocelyne Just, Nicole Le Moual, Pierre Scheinmann, Valérie Siroux, Daniel Vervloet, Diana Zelenika, Isabelle Pin, Francine Kauffmann, Mark Lathrop, Florence Demenais, Effect of 17q21 variants and smoking exposure in early-onset asthma. The New England Journal of Medicine. ,vol. 359, pp. 1985- 1994 ,(2008) , 10.1056/NEJMOA0806604
Manan M. Mehta, Shirley Liu, Jonathan J. Silberg, A transposase strategy for creating libraries of circularly permuted proteins Nucleic Acids Research. ,vol. 40, ,(2012) , 10.1093/NAR/GKS060
G. R. Wilson, H. X. Wang, G. F. Egan, P. J. Robinson, M. B. Delatycki, M. K. O'Bryan, P. J. Lockhart, Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse Human Molecular Genetics. ,vol. 19, pp. 1593- 1602 ,(2010) , 10.1093/HMG/DDQ031
Miriam F Moffatt, Ivo G Gut, Florence Demenais, David P Strachan, Emmanuelle Bouzigon, Simon Heath, Erika von Mutius, Martin Farrall, Mark Lathrop, William OCM Cookson, None, A large-scale, consortium-based genomewide association study of asthma. The New England Journal of Medicine. ,vol. 363, pp. 1211- 1221 ,(2010) , 10.1056/NEJMOA0906312