title: ITGB5 and AGFG1 variants are associated with severity of airway responsiveness.
abstract: BACKGROUND
  Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.
  
  
  METHODS
  A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects.
  
  
  RESULTS
  The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1.
  
  
  CONCLUSIONS
  Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. blanca.himes@channing.harvard.edu.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Himes
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: John
authors.initials: J
authors.lastname: Ziniti
authors.forename: Jody
authors.initials: J
authors.lastname: Senter-Sylvia
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lemanske
authors.forename: Robert S
authors.initials: RS
authors.lastname: Zeiger
authors.forename: Robert C
authors.initials: RC
authors.lastname: Strunk
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.forename: Homer
authors.initials: H
authors.lastname: Boushey
authors.forename: Vernon M
authors.initials: VM
authors.lastname: Chinchilli
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.forename: David
authors.initials: D
authors.lastname: Mauger
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.forename: Maartje A E
authors.initials: MA
authors.lastname: Nieuwenhuis
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.forename: Judith M
authors.initials: JM
authors.lastname: Vonk
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rafaels
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Hansel
authors.forename: Kathleen
authors.initials: K
authors.lastname: Barnes
authors.forename: Benjamin
authors.initials: B
authors.lastname: Raby
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000483:Alleles; D001249:Asthma / Q000235:genetics* / Q000473:pathology; D001827:Body Height; D002648:Child; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D039641:Integrin beta Chains / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D016601:RNA-Binding Proteins / Q000235:genetics*; D012737:Sex Factors
chemical_list: C119724:AGFG1 protein, human; D039641:Integrin beta Chains; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; C084344:integrin beta5