Leukotriene B 4} production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with risk of myocardial infarction
Résumé
Leukotrienes are implicated in the pathogenesis of coronary artery disease. Recently two haplotypes (Hap A and Hap B) in the gene encoding arachidonate 5-lipoxygenase activating protein (ALOX5AP), 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 for coronary risk in patients carrying HapA, raising the possibility of developing genotype-specific therapy. In this study, we examined whether carriage of HapA or HapB is associated with increased leukotriene B 4} (LTB 4}) production in healthy subjects. Age and gender-matched healthy HapA carriers (n = 21), HapB carriers (n = 20) and nonA/nonB 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 measured in response to stimulation with 1microM of the calcium ionophore A23187. There was no difference in the mean level for LTB 4} production in the three groups (nonA/nonB: 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 increase 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 likely clinical response to ALOX5AP inhibitors.
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