title: Genetic variation in vascular endothelial growth factor-a and lung function.
abstract: BACKGROUND
  Given the role of vascular endothelial growth factor (VEGF) in lung development, we hypothesized that polymorphisms in VEGF-A may be associated with lung function.
  
  
  OBJECTIVE
  The current study was designed to assess the role of genetic variants in VEGF-A as determinants of airway function from infancy through early adulthood.
  
  
  METHODS
  Association between five single-nucleotide polymorphisms (SNPs) in VEGF-A and lung function were assessed longitudinally in two unselected birth cohorts and cross-sectionally among infants. Replication with two SNPs was conducted in adults and children with asthma. We investigated the functionality of the SNP most consistently associated with lung function (rs3025028) using Western blotting to measure the ratio of plasma VEGF-A(165b)/panVEGF-A(165) among homozygotes.
  
  
  RESULTS
  In two populations in infancy, C-allele homozygotes of rs3025028 had significantly higher VmaxFRC, forced expiratory flow(50), and forced expiratory flow(25-75) compared with other genotype groups. Among preschool children (age 3 yr), C allele of rs3025028 was associated with significantly higher specific airway conductance, with similar findings observed for lung function in school-age children. For FEV(1)/FVC ratio similar findings were observed among adolescents and young adults (birth cohort), and then replicated in adults and schoolchildren with asthma (cross-sectional studies). For rs3025038, plasma VEGF-A(165b)/panVEGF-A(165) was significantly higher among CC versus GG homozygotes (P ≤ 0.02) at birth, in school-age children, and in adults.
  
  
  CONCLUSIONS
  We report significant associations between VEGF-A SNP rs3025028 and parameters of airway function measured throughout childhood, with the effect persisting into adulthood. We propose that the mechanism may be mediated through the ratios of active and inhibitory isoforms of VEGF-A(165), which may be determined by alternative splicing.
authors.affiliation: University of Manchester, Wythenshawe Hospital, Manchester, UK. angela.simpson@manchester.ac.uk
authors.forename: Angela
authors.initials: A
authors.lastname: Simpson
authors.forename: Adnan
authors.initials: A
authors.lastname: Custovic
authors.forename: Robert
authors.initials: R
authors.lastname: Tepper
authors.forename: Penelope
authors.initials: P
authors.lastname: Graves
authors.forename: Debra A
authors.initials: DA
authors.lastname: Stern
authors.forename: Marcus
authors.initials: M
authors.lastname: Jones
authors.forename: Jenny
authors.initials: J
authors.lastname: Hankinson
authors.forename: John A
authors.initials: JA
authors.lastname: Curtin
authors.forename: Jiakai
authors.initials: J
authors.lastname: Wu
authors.forename: Mario
authors.initials: M
authors.lastname: Blekic
authors.forename: Blazenka Kljaic
authors.initials: BK
authors.lastname: Bukvic
authors.forename: Neda
authors.initials: N
authors.lastname: Aberle
authors.forename: Susana
authors.initials: S
authors.lastname: Marinho
authors.forename: Danielle
authors.initials: D
authors.lastname: Belgrave
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Morgan
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000483:Alleles; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012129:Respiratory Function Tests; D018570:Risk Assessment; D012720:Severity of Illness Index; D014109:Total Lung Capacity / Q000235:genetics; D006113:United Kingdom; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D014797:Vital Capacity / Q000235:genetics
chemical_list: D042461:Vascular Endothelial Growth Factor A