The c.-292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective.
BACKGROUND
Reticulocyte-type 15-lipoxygenase-1 (ALOX15) has anti-inflammatory and inflammatory effects and is implicated in the development of asthma, arthritis and atherosclerosis. Previously, we screened the human ALOX15 gene for variations because genetic variability in ALOX15 might influence these diseases. We found a C>T substitution at position c.-292 in the ALOX15 promoter that created a novel binding site for the transcription factor SPI1 and increased ALOX15 mRNA levels in monocytes from c.-292CT heterozygous volunteers.


METHODS
To test whether the higher mRNA levels led to higher ALOX15 activity, we performed an activity assay and measured the arachidonic acid metabolite 15(S)-hydroxy-eicosatetraenoic acid [15(S)-HETE] by HPLC analysis. To test whether this polymorphism was associated with coronary artery disease (CAD), we investigated its association in a case-control study involving 498 Caucasians.


RESULTS
The c.-292C>T polymorphism was associated with higher enzyme activity in heterozygous carriers. Intriguingly, this polymorphism also showed a tendency to be protective against atherosclerosis.


CONCLUSIONS
These results suggest that increased ALOX15 activity may attenuate inflammation, which could be caused by an increase in 15(S)-HETE and eventually by its metabolites, the lipoxins.
Wittwer
Jonas
J
Institute of Clinical Chemistry, Center for Integrative Human Physiology, University Hospital Zurich, Zurich, Switzerland.
Bayer
Mathias
M
Mosandl
Armin
A
Muntwyler
Jörg
J
Hersberger
Martin
M
D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000517:prevention & control*; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D003324:Coronary Artery Disease / Q000235:genetics; D003596:Cytosine / Q000737:chemistry*; D005260:Female; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013941:Thymine / Q000737:chemistry*
D012333:RNA, Messenger; D003596:Cytosine; D001093:Arachidonate 15-Lipoxygenase; D013941:Thymine