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

• Published in: Clinical science (1979) Vol. 112; no. 7; pp. 411 - 416
• Main Authors: Maznyczka, Annette, Mangino, Massimo, Whittaker, Andrew, Braund, Peter, Palmer, Tom, Tobin, Martin, Goodall, Alison H., Bradding, Peter, Samani, Nilesh J.
• Format: Journal Article
• Language: English
• Published: London Portland Press 01.06.2007
• Subjects: 5-Lipoxygenase-Activating Proteins; Analysis of Variance; Arachidonate 5-Lipoxygenase - metabolism; Biological and medical sciences; Calcimycin - pharmacology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Epidemiology; Female; General aspects; Genetic Predisposition to Disease; Haplotypes; Heterozygote; Humans; Ionophores - pharmacology; Leukotriene B4 - biosynthesis; Male; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Middle Aged; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Neutrophils - drug effects; Neutrophils - metabolism; Polymorphism, Single Nucleotide; Public health. Hygiene; Public health. Hygiene-occupational medicine; Risk Factors; Stimulation, Chemical; Myocardial infarction; Genetic variability; Healthy subject; Cardiovascular disease; Genotype; Risk; Myocardial disease; Epidemiology; Medicine; Variant; Association; Leukotriene B4; Heart disease; Risk factor; Production; ALOX5AP gene
• ISSN: 0143-5221; 1470-8736; 1470-8736
• DOI: 10.1042/CS20060271

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 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 μmol/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.