ALOX5 promoter genotype, asthma severity and LTC₄ production by eosinophils

Background: The number of Sp1-Egr1 binding tandem repeats at the ALOX5 promoter influences gene transcription and may modify the response to anti-leukotriene treatment. The relationship of ALOX5 variants to asthma severity and leukotriene production by eosinophils is unknown. Objective: To characterize ALOX5 mRNA expression and cysteinyl-leukotriene production by eosinophils from individuals bearing ALOX5 promoter deletional variants and their association with the severity of childhood asthma. Methods: Eosinophils from adult asthmatics bearing only variant alleles (with other than five tandem repeats on both chromosomes, non5/non5) or no variant alleles (5/5) were cultured in vitro and ALOX5 expression and leukotriene secretion were measured. A total of 621 children with mild or moderate-severe asthma were genotyped at the ALOX5 core promoter. Results: Asthmatics with non5/non5 genotype expressed less ALOX5 mRNA and produced less LTC4 into culture supernatants than 5/5 individuals (6.4 ± 2.0 and 20.0 ± 5.0 pg/ml, n = 5; P < 0.05). More asthmatic children bearing non5/non5 genotype had moderate-severe asthma than children with the 5/5 genotype (5.3% vs. 1.4%, P = 0.008). Multivariate logistic regression identified ALOX5 promoter genotype as a significant predictor of disease severity (OR = 3.647, 95% CI: 1.146-11.608, P = 0.03). Consistent with these findings, children bearing the non5/non5 genotype had greater bronchomotor response to exercise as measured by the maximum fall after exercise and the area under the exercise curve (P < 0.05 for both). Conclusion: Our results suggest that children who express the asthma phenotype despite having a genetic variant that impairs their ability to express ALOX5 have more severe disease and thus are more likely to have asthma symptoms.