Objective: Myeloperoxidase catalyzes the formation of reactive oxygen metabolites in neutrophils and monocytes. Increased plasma myeloperoxidase concentrations are linked to coronary artery stenosis and may be useful for risk prediction following acute coronary syndromes. We studied the influence of the - 129 G>A and - 463 G>A myeloperoxidase gene promoter polymorphisms on myeloperoxidase concentrations and reactive oxygen metabolite production after neutrophil stimulation.
Methods: Neutrophils from 305 healthy blood donors were stimulated with N-Formyl-Met-Leu-Phe or phorbol-myristate-acetate. Plasma myeloperoxidase concentrations were quantified by enzyme immunoassay and reactive oxygen metabolites by flow cytometry. Genotyping was performed by PCR and restriction fragment length analysis.
Results: The - 129 A allele was associated with lower myeloperoxidase concentrations in unstimulated blood (P< 0.05), but the variation among the genotypes was small. Plasma myeloperoxidase was unrelated to the - 463 G> A polymorphism. Baseline myeloperoxidase was associated with use of sex hormones in women, but not with sex, age, smoking habits or use of nonsteroid anti-inflammatory medication. The polymorphisms were not associated with the change from baseline in myeloperoxidase or reactive oxygen metabolites after neutrophil stimulation. Control experiments on myeloperoxidase function in cell lysates from 50 additional donors confirmed the results.
Conclusion: The - 129 A allele was associated with slightly lower myeloperoxidase plasma concentrations. The - 129 G>A and - 463 G>A polymorphisms did not affect myeloperoxidase degranulation or reactive oxygen metabolite production after neutrophil activation. It therefore seems unlikely that they are mechanistically related to the risk for atherosclerosis. Our findings may explain why associations between these polymorphisms and cardiovascular disease have been difficult to reproduce.