Promoter polymorphism in the 5-lipoxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) genes and asthma susceptibility in a Caucasian population.
BACKGROUND
5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are essential for cysteinyl-leukotriene (cys-LT) production, critical mediators in asthma.


OBJECTIVE
We sought to identify novel promoter polymorphisms within the FLAP (ALOX5AP) gene promoter and test the role of these and the previously identified 5-LO (ALOX5) Sp1 promoter polymorphism in asthma susceptibility.


METHODS
To assess genetic association with asthma phenotypes, we genotyped 341 Caucasian families (containing two asthmatic siblings) and non-asthmatic control subjects (n=184). Genetic association was determined by case-control and transmission disequilibrium test (TDT) analyses. To determine the functional role of polymorphisms on basal transcription, we generated ALOX5AP-promoter-luciferase constructs and transiently transfected human HeLa cells.


RESULTS
A novel G/A substitution at -336 bp and a poly(A) repeat (n=19 or 23) at position -169 to -146 bp were identified in the ALOX5AP promoter. Genotyping found the -336 A and poly(A19) alleles at frequencies of q=0.06 and 0.12, respectively. No ALOX5AP allele was associated with asthma or asthma-related phenotypes in case-control or TDT analyses. ALOX5AP-promoter-luciferase analyses did not support a functional role of the -336 or poly(A) polymorphism in determining basal transcription. The ALOX5 Sp1 polymorphism was predominantly homozygous wild-type 5/5 (frequency q=0.70) and heterozygous 4/5 (q=0.23) genotypes and no allele was associated with asthma or asthma-related phenotypes.


CONCLUSIONS
Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.
Sayers
I
I
Divisions of Human Genetics Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton General Hospital, Tremona Road, Southampton, UK.
Barton
S
S
Rorke
S
S
Sawyer
J
J
Peng
Q
Q
Beghé
B
B
Ye
S
S
Keith
T
T
Clough
J B
JB
Holloway
J W
JW
Sampson
A P
AP
Holgate
S T
ST
D058927:5-Lipoxygenase-Activating Proteins; D000293:Adolescent; D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D001249:Asthma / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010375:Pedigree; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D014162:Transfection
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D001094:Arachidonate 5-Lipoxygenase; D008156:Luciferases