title: ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma.
abstract: BACKGROUND
  Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy, but its impact on disease control remains unclear.
  
  
  OBJECTIVE
  We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score.
  
  
  METHODS
  We analysed 270 children, 6- to 17-years old, with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels.
  
  
  RESULTS
  Of all children, 14.8% (40/270) (and 28% (38/135) of African Americans) carried two non-5-repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 vs. 30 nmol/mol creatinine, P = 0.0134), significantly worse FEV1% predicted (84 vs. 91, P = 0.017) and a trend towards worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (r = -0.192, P = 0.009).
  
  
  CONCLUSIONS
  Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.
authors.affiliation: Center for Pharmacogenomics & Translational Research, Nemours Children's Clinic, Jacksonville, FL 32207, USA.
authors.forename: E
authors.initials: E
authors.lastname: Mougey
authors.forename: J E
authors.initials: JE
authors.lastname: Lang
authors.forename: H
authors.initials: H
authors.lastname: Allayee
authors.forename: W G
authors.initials: WG
authors.lastname: Teague
authors.forename: A J
authors.initials: AJ
authors.lastname: Dozor
authors.forename: R A
authors.initials: RA
authors.lastname: Wise
authors.forename: J J
authors.initials: JJ
authors.lastname: Lima
mesh_terms: D000293:Adolescent; D000483:Alleles; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D001249:Asthma / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D001665:Binding Sites; D002648:Child; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D017999:Leukotriene E4 / Q000652:urine; D015289:Leukotrienes / Q000096:biosynthesis* / Q000652:urine; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012129:Respiratory Function Tests; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D015289:Leukotrienes; D016329:Sp1 Transcription Factor; D017999:Leukotriene E4; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human