Vonk J M, Scholtens S, Postma D S, Moffatt M F, Jarvis D, Ramasamy A, Wjst M, Omenaas E R, Bouzigon E, Demenais F, Nadif R, Siroux V, Polonikov A V, Solodilova M, Ivanov V P, Curjuric I, Imboden M, Kumar A, Probst-Hensch N, Ogorodova L M, Puzyrev V P, Bragina E Yu, Freidin M B, Nolte I M, Farrall A M, Cookson W O C M, Strachan D P, Koppelman G H, Boezen H M
University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.
University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, the Netherlands.
PLoS One. 2017 Mar 2;12(3):e0172716. doi: 10.1371/journal.pone.0172716. eCollection 2017.
Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma.
We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects.
First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.6310-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.2110-4; replication: ORint = 1.40, p = 0.03).
Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.
全基因组关联研究已确定了哮喘的新型遗传关联，但未考虑当前吸烟的作用。本研究旨在识别与成人哮喘中当前吸烟相互作用的新基因。
我们在参与GABRIEL联盟的六项研究中，基于1）总体相互作用效应和2）有吸烟暴露和无吸烟暴露受试者的遗传效应，采用两种荟萃分析方法进行了全基因组相互作用分析。我们进行了一项发现性荟萃分析，纳入了4057名欧洲血统受试者，并在一个独立队列（生命线队列研究）中对我们的发现进行了重复验证，该队列包括12475名受试者。
第一种方法：基于p<10-4的总体相互作用效应选择了50个单核苷酸多态性（SNP）。在9号染色体上观察到rs9969775的相互作用效应最为显著（发现性荟萃分析：ORint = 0.50，p = 7.63×10-5，重复验证：ORint = 0.65，p = 0.02）。第二种方法：基于暴露受试者的总体遗传效应选择了35个SNP（p <10-4）。在12号染色体上观察到rs5011804的遗传效应最为显著（发现性荟萃分析ORint = 1.50，p = 1.21×10-4；重复验证：ORint = 1.40，p = 0.03）。
通过两种全基因组相互作用方法，我们在9号和12号染色体上未注释的基因间区域中识别出了新的多态性，这些多态性显示出在成人哮喘发病中与当前吸烟相互作用的提示性证据。
