title: 17q12-21 variants are associated with asthma and interact with active smoking in an adult population from the United Kingdom.
abstract: BACKGROUND
  Although an association between 17q12-21 and asthma has been replicated across different populations, some inconsistencies have been found between different studies.
  
  
  OBJECTIVE
  We investigated the association between genetic variation in this region with asthma, lung function, airway inflammation, hyperresponsiveness (AHR), and atopy in a case-control study of United Kingdom adults. The interaction between genotype and smoking was also evaluated.
  
  
  METHODS
  Study subjects (n = 983) were carefully phenotyped using questionnaires, measurement of lung function, AHR (methacholine challenge), exhaled nitric oxide (eNO), and assessment of atopic status. Blood/saliva/buccal swabs were collected, and 47 single nucleotide polymorphisms (SNPs) in 17q12-21 were genotyped using MALDI-TOF (Matrix-assisted LASER desorption/ionisation-time of flight) mass spectrometry. We conducted a comprehensive investigation of 28 common SNPs within 6 genes of interest (IKZF3, ZPBP2, ORMDL3, GSDMA, GSDMB, TOP2A).
  
  
  RESULTS
  Sixteen SNPs were significantly associated with asthma after multiple testing correction (P ≤ .01), of which 5 (rs2290400, rs8079416, rs3894194, rs7212938, and rs3859192) were strongly associated (FDR P ≤ .0002), and one was novel (IKZF3-rs1453559). For 3 of these SNPs, we found significant interaction with smoking and asthma (rs12936231, rs2290400, and rs8079416). Smoking modified the associations between 8 SNPs and lung function (rs9911688, rs9900538, rs1054609, rs8076131, rs3902025, rs3859192, rs11540720, and rs11650680). We observed significant interaction between 5 SNPs and smoking on AHR, and 3 interacted with smoking in relation to asthma with AHR (rs4795404, rs4795408, rs3859192).
  
  
  CONCLUSIONS
  We found 1 novel association and replicated several previously reported associations between 17q12-21 polymorphisms and asthma. We demonstrated significant interactions between active smoking and polymorphisms in 17q12-21 with asthma, lung function, and AHR in adults. Our data confirm that 17q12-21 is an important asthma susceptibility locus.
authors.affiliation: Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, The University of Manchester, United Kingdom. susana.marinho@manchester.ac.uk
authors.forename: Susana
authors.initials: S
authors.lastname: Marinho
authors.forename: Adnan
authors.initials: A
authors.lastname: Custovic
authors.forename: Paul
authors.initials: P
authors.lastname: Marsden
authors.forename: Jacky A
authors.initials: JA
authors.lastname: Smith
authors.forename: Angela
authors.initials: A
authors.lastname: Simpson
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D016022:Case-Control Studies; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics* / Q000276:immunology; D005260:Female; D056426:Genetic Loci / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology; D015810:Linkage Disequilibrium; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012129:Respiratory Function Tests; D012907:Smoking / Q000009:adverse effects* / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D011795:Surveys and Questionnaires; D006113:United Kingdom
chemical_list: C106285:IKZF3 protein, human; D051740:Ikaros Transcription Factor