Is Vascular Inflammation Predetermined? Insights from Lipoxygenase Polymorphisms

Robert S. Rosenson, M.D.

Vessel wall inflammation mediates the initiation and progression of atherosclerosis and acute thrombotic complications [1]. This process involves the recruitment, retention, and accumulation of monocyte derived macrophages. Macrophages, dendritic cells, and the less often involved mast cells perpetuate the inflammatory response through the release of chemokines and cytokines.

Leukotrienes (LT) represent a class of eicosanoids that are derived from the action of 5-lipoxygenase (5-LO). This enzyme is expressed in monocytes, macrophages, dendritic cells and mast cells. 5-LO convents arachidonic acid to LTA4 [2], which is converted to LTB4. LTB4 is a potential chemoattractant for macrophages and induces adhesion of monocytes and T cells to the vascular endothelium. LTB4 is conjugated with glutathione to form the cysteinyl leukotriene LTC4. Cysteinyl leukotrienes increase vascular permeability and induce vasoconstriction.

5-LO contributes to the oxidation of LDL, which serves as the primary ligand for nuclear receptors that activate inflammatory genes. 5-LO is common in advanced lesions [3], and it accumulates in sites that are most prone to rupture [3]. Elevated levels of inflammatory mediators and markers identify individuals at high-risk for atherosclerosis and cardiovascular events [4].

The genetic basis for the arterial wall inflammation was explored in two recent studies. Variant 5-LO genotypes (ALOX5) promoter were detected in 6.0% of 470 healthy, middle aged men and women enrolled in the Los Angles Atherosclerosis Study [5]. In multivariate analyses, the intima-media thickness was increased in carriers of two variant alleles by 80 ± 19 mm as compared with carriers of the common allele (odds ratio, 4.1; 95% CI: 2.1 to 8.2; p < 0.001).

A four-marker single-nucleotide polymorphism (SNP) haplotype in the locus spanning the gene ALOX5AP that encodes the 5-lipoxganase activating protein was associated with an increased risk of myocardial infarction and stroke in a genomic wide scan in two populations [2]. In 713 Icelandic individuals myocardial infarction and 837 population-based controls, HapA has a frequency of 15.8% in affected individuals versus 9.5% in controls. HapA was associated with a 1.8-fold increased risk of myocardial infarction and stroke. The population attributable risk associated with HapA was 3.5%. In a British cohort that included 753 individuals with myocardial infarction and 730 British controls, there was a non-significant increase in HapA prevalence among myocardial infarction survivors. In contrast, HapB a distinct and mutually exclusive haploid was detected in 7.5% of individuals with myocardial infarction with 4.0% of controls (relative risk of 1.95).

These studies identify 5-LO polymorphisms that are associated with an increased risk. These polymorphisms may contribute to cardiovascular disease through increased LT production and vascular inflammation. Further studies of atherosclerosis, myocardial infarction, and stroke are needed to characterize the genetic susceptibility to vascular inflammation.

References:

1. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003;108:1664-1672.
2. Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004;36:233-239.
3. Spanbroek R, Grabner R, Lotzer K, et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci U S A. 2003;100:1238-1243.
4. Koenig W, Rosenson R. Emerging Risk Factors: Acute-Phase Reactants. Supplement on risk factors for coronary heart disease. Sem Vasc Med. 2002;2:417-428.
5. Dwyer JH, Allayee H, Dwyer KM, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med. 2004;350:29-37.