title: Assessing the validity of asthma associations for eight candidate genes and age at diagnosis effects.
abstract: BACKGROUND
  Before the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis.
  
  
  RESULTS
  We systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R.
  
  
  CONCLUSIONS
  Our results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain ; Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Pino-Yanes
authors.forename: Almudena
authors.initials: A
authors.lastname: Corrales
authors.forename: José
authors.initials: J
authors.lastname: Cumplido
authors.forename: Paloma
authors.initials: P
authors.lastname: Poza
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Sánchez-Machín
authors.forename: Anselmo
authors.initials: A
authors.lastname: Sánchez-Palacios
authors.forename: Javier
authors.initials: J
authors.lastname: Figueroa
authors.forename: Orlando
authors.initials: O
authors.lastname: Acosta-Fernández
authors.forename: Nisa
authors.initials: N
authors.lastname: Buset
authors.forename: José Carlos
authors.initials: JC
authors.lastname: García-Robaina
authors.forename: Mariano
authors.initials: M
authors.lastname: Hernández
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
authors.forename: Teresa
authors.initials: T
authors.lastname: Carrillo
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D001249:Asthma / Q000175:diagnosis* / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002874:Chromosome Mapping; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017455:Receptors, IgE / Q000235:genetics; D055815:Young Adult
chemical_list: C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; C502447:MS4A2 protein, human; D017455:Receptors, IgE; D051722:ADAM Proteins; C450441:ADAM33 protein, human
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