ALOX5 promoter genotype, asthma severity and LTC 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).


CONCLUSIONS
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.
Kalayci
O
O
Hacettepe University School of Medicine, Pediatric Allergy and Asthma Unit, Hacettepe, Ankara, Turkey.
Birben
E
E
Sackesen
C
C
Keskin
O
O
Tahan
F
F
Wechsler
M E
ME
Civelek
E
E
Soyer
O U
OU
Adalioglu
G
G
Tuncer
A
A
Israel
E
E
Lilly
C
C
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001249:Asthma / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D017997:Leukotriene C4 / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011336:Probability; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D012129:Respiratory Function Tests; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D012737:Sex Factors; D016037:Single-Blind Method; D018709:Statistics, Nonparametric
D012333:RNA, Messenger; D017997:Leukotriene C4; D001094:Arachidonate 5-Lipoxygenase