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.
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.
Authors: Charles B Stephensen; Patrice Armstrong; John W Newman; Theresa L Pedersen; Jillian Legault; Gertrud U Schuster; Darshan Kelley; Susanna Vikman; Jaana Hartiala; Rami Nassir; Michael F Seldin; Hooman Allayee Journal: J Lipid Res Date: 2011-02-04 Impact factor: 5.922
Authors: Sarah E Kleinstein; Laura Heath; Karen W Makar; Elizabeth M Poole; Brenna L Seufert; Martha L Slattery; Liren Xiao; David J Duggan; Li Hsu; Karen Curtin; Lisel Koepl; Jill Muehling; Darin Taverna; Bette J Caan; Christopher S Carlson; John D Potter; Cornelia M Ulrich Journal: Genes Chromosomes Cancer Date: 2013-02-12 Impact factor: 5.006
Authors: Jelle Folkerts; Frank Redegeld; Gert Folkerts; Bart Blokhuis; Mariska P M van den Berg; Marjolein J W de Bruijn; Wilfred F J van IJcken; Tobias Junt; See-Ying Tam; Stephen J Galli; Rudi W Hendriks; Ralph Stadhouders; Marcus Maurer Journal: Allergy Date: 2020-04-24 Impact factor: 13.146