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: Medicine 、 Genetics 、 Candidate gene 、 Tobacco smoke 、 Passive smoking 、 Missing heritability problem 、 Single-nucleotide polymorphism 、 Immunology 、 Genetic predisposition 、 Asthma 、 Motile 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.