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Leukotriene B4 production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction

By Annette Maznyczka, Massimo Mangino, Andrew Whittaker, Peter S. Braund, Thomas M. Palmer, Martin D. Tobin, Alison H. Goodall, Peter Bradding and Nilesh J. Samani

Abstract

This paper was published as Clinical Science, 2007, 112 (7), pp. 411-416. It is available from http://www.clinsci.org/cs/112/cs1120411.htm. Doi: 10.1042/CS20060271Metadata only entryLeukotrienes 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 LTB4 (leukotriene B4) 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 LTB4 production was measured in response to stimulation with 1 mmol/l of the calcium ionophore A23187. There was no difference in the mean level for LTB4 production in the three groups (non-A/non-B, 24.9±8.3 ng/106 cells; HapA, 22.2±11.9 ng/106 cells; HapB, 19.8±4.8 ng/106; 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 LTB4 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

Publisher: Portland Press
Year: 2007
DOI identifier: 10.1042/CS20060271
OAI identifier: oai:lra.le.ac.uk:2381/7339
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