Leukotriene B4 production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction.
Leukotrienes are implicated in the pathogenesis of coronary artery disease. Recently two haplotypes (HapA and HapB) in the gene encoding ALOX5AP (arachidonate 5-lipoxygenase-activating protein), the main regulator of 5-lipoxygenase, have been associated with a doubling of the risk of myocardial infarction. Studies have also shown that treatment with a leukotriene inhibitor reduces biomarkers of coronary risk in patients carrying HapA, raising the possibility of developing genotype-specific therapy. In the present study, we examined whether carriage of HapA or HapB is associated with increased LTB(4) (leukotriene B(4)) production in healthy subjects. Age- and gender-matched healthy HapA carriers (n=21), HapB carriers (n=20) and non-A/non-B carriers (n=18), with no reported history of cardiovascular disease, were recruited following DNA screening of 1268 subjects from a population-based study. Blood neutrophils were isolated, and LTB(4) production was measured in response to stimulation with 1 mumol/l of the calcium ionophore A23187. There was no difference in the mean level for LTB(4) production in the three groups (non-A/non-B, 24.9+/-8.3 ng/10(6) cells; HapA, 22.2+/-11.9 ng/10(6) cells; HapB, 19.8+/-4.8 ng/10(6); P=0.14). The findings indicate that if either the HapA or the HapB haplotype of ALOX5AP indeed increases cardiovascular risk, then the mechanism is not simply due to a systematically observable effect of the haplotype on LTB(4) production in response to stimulation. The results suggest that knowledge of a patient's haplotype may not provide useful information on the probable clinical response to ALOX5AP inhibitors.
Maznyczka
Annette
A
Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK.
Mangino
Massimo
M
Whittaker
Andrew
A
Braund
Peter
P
Palmer
Tom
T
Tobin
Martin
M
Goodall
Alison H
AH
Bradding
Peter
P
Samani
Nilesh J
NJ
D058927:5-Lipoxygenase-Activating Proteins; D000704:Analysis of Variance; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013268:Stimulation, Chemical
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D007476:Ionophores; D008565:Membrane Proteins; D007975:Leukotriene B4; D000001:Calcimycin; D001094:Arachidonate 5-Lipoxygenase