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).

Conclusion and clinical relevance: 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.

© 2012 Blackwell Publishing Ltd.

Figures

Figure 1. Urinary LTE4 Levels by ALOX5 Promoter Genotype

Urinary LTE4 by genotype for marker rs59439148 in all patients (white bars), in African American patients (light gray bars) and in White patients (dark gray bars). None of the White participants had x/x genotype. Bars represent geometric mean with error bars representing 95% confidence limits. Urine samples were collected at week 24 of the study. Values that differ significantly by genotype are indicated with ‘*’ (p-value

Figure 2. Forced Expiratory Volume in 1 Second by ALOX5 Promoter Genotype

Mean FEV1%pred genotype for marker rs59439148 in all patients (white bars), in African American patients (light gray bars) and in White patients (dark gray bars). None of the White participants had x/x genotype. Bars represent mean with error bars representing 95% confidence limits. Lung function data were collected at week 24 of the study. Values that differ significantly by genotype are indicated with ‘*’ (p-value

Figure 3. FEV1 percent predicted is plotted as a function of uLTE4

Data is taken from all asthmatic patients (n=183) with both a valid FEV1%pred value and uLTE4 level at the final visit. Zero suppression is present on the y-axis. r = -0.192, p = .009.