ALOX5AP variants are associated with in-stent restenosis after percutaneous coronary intervention

Shah, Svati H.; Hauser, Elizabeth R.; Crosslin, David R.; Wang, Liyong; Haynes, Carol; Connelly, Jessica J.; Nelson, Sarah C.; Johnson, Jessica; Gadson, Shera; Nelson, Charlotte L.; Seo, David; Gregory, Simon G.; Kraus, William E.; Granger, Christopher B.; Goldschmidt‐Clermont, Pascal J.; Newby, L. Kristin

doi:10.1016/j.atherosclerosis.2008.01.011

Cited by 20 publications

(17 citation statements)

References 25 publications

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“…Consistent with this notion, variations in genes of the LT biosynthetic pathway have been associated with increased CVD risk (14)(15)(16)(17)(18), although some studies have reported equivocal results or no association (19)(20)(21). The promoter region of the ALOX5 gene has between three and eight tandem repeats of a consensus binding site for the transcription factors Sp1 and Egr1, with the most frequent allele having fi ve such repeats ( 22 ).…”

Section: Ethical Review and Trial Registrationmentioning

confidence: 53%

ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation

Stephensen

Armstrong

Newman

et al. 2011

Journal of Lipid Research

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Eicosanoids, including leukotrienes (LT), are products of arachidonic acid (AA) metabolism that mediate infl ammation during infectious, allergic, and other infl ammatory diseases ( 1 ), including cardiovascular disease (CVD) ( 2 ). The ALOX5 gene encodes the 5-lipoxygenase (5-LO) enzyme, which acts with 5-lipoxygenase activating protein (FLAP) to catalyze the fi rst two steps in LT synthesis, the production of 5-hydroperoxyeicosatetraenoate (5-HpETE), followed by its conversion to LTA4 or its glutathione peroxidase-dependent conversion to 5-hydroxyeicosatetraenoate (5-HETE) ( 3 ). 5-HETE is a bioactive semistable metabolite that reversibly forms a lactone (5-hydroxy-6 dlactone) ( 4, 5 ) and is also converted by 5-hydroxyeicosanoid dehydrogenase (5-HEDH) to the active metabolite 5-oxo -ETE ( 6 ). LTA4 is unstable ( 7 ) , 5-oxo -ETE, 15-HETE, and 5,15-diHETE levels were higher in subjects homozygous for the ALOX5 promoter allele containing fi ve Sp1 element tandem repeats ("55" genotype) than in subjects with one deletion (d) (three or four repeats) and one common ("d5" genotype) allele or with two deletion ("dd") alleles. The EPA-derived metabolites 5-HEPE and 15-HEPE and the DHA-derived metabolite 17-HDoHE had similar associations with genotype and increased with supplementation; 5-HEPE and 15-HEPE increased, and 5-oxo -ETE decreased to a greater degree in the 55 than in the other genotypes. This differential eicosanoid response is consistent with the previously observed interaction of these variants with dietary intake of omega-3 fatty acids in predicting cardiovascular disease risk. -

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Section: Ethical Review and Trial Registrationmentioning

confidence: 53%

ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation

Stephensen

Armstrong

Newman

et al. 2011

Journal of Lipid Research

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“…3 Furthermore, the polymorphisms within the gene encoding the 5-LO activating protein (FLAP), which have been associated with an increased risk of myocardial infarction and stroke, 4 were recently reproduced in restenosis patients. 5 In the latter study, 2 of the FLAP gene polymorphisms studied were independent prognostic factors in predicting in-stent restenosis 6 months after PCI. 5 Although no previous study has evaluated the effects of antileukotrienes on in-stent restenosis, the available data have provided indications for potential effects of LTs in the response to vascular injury.…”

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confidence: 99%

“…5 In the latter study, 2 of the FLAP gene polymorphisms studied were independent prognostic factors in predicting in-stent restenosis 6 months after PCI. 5 Although no previous study has evaluated the effects of antileukotrienes on in-stent restenosis, the available data have provided indications for potential effects of LTs in the response to vascular injury. 3 For example, LTB 4 induces migration and proliferation of human coronary artery vascular smooth muscle cells (VSMCs).…”

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Leukotriene Receptor Antagonism and the Prevention of Extracellular Matrix Degradation During Atherosclerosis and In-Stent Stenosis

Hlawaty

Jacob

Louedec

et al. 2009

ATVB

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Objective-The lipid-derived inflammatory mediators leukotrienes (LTs) are produced during vascular injury. The aim of the present study was to determine the role of LT receptor signaling in the pathophysiology of in-stent stenosis. Methods and Results-New Zealand White rabbits were fed 0.3% cholesterol and subjected to angioplasty with balloon dilatation and stent implantation in the right carotid artery. Rabbits treated for 2 weeks with the BLT receptor antagonist BIIL284 (3 mg/kg once daily by oral gavage) displayed a significantly reduced in-stent intimal hyperplasia in carotid arteries compared with vehicle-treated rabbits. In addition, BIIL284 treatment significantly reduced the extracellular matrix metalloproteinase (MMP)-2 and MMP-9 activities in stented arteries. The inhibited MMP-9 activity was correlated with decreased macrophage content in the lesions. The LTB 4 -induced migration of vascular smooth muscle cells was significantly inhibited by transfection with siRNA against MMP-2. Finally, human arteries subjected to ex vivo angioplasty and stent implantation displayed an increased in-stent intimal hyperplasia and higher MMP-2 and -9 activities in the presence of LTB 4 . T he use of stents in percutaneous coronary interventions (PCI) has reduced the incidence of restenosis, particularly in combination with local administration of cell cycle inhibiting rapamycin derivates by means of drug eluting stents (DES). However, the use of DES in interventional cardiology has also been associated with an increased risk of late stent thrombosis. 1 Such side-effects suggest the importance of identifying novel targets for both local and systemic treatment, which have an inhibitory effect on in-stent restenosis. Conclusions-TheseInterestingly, PCI is a stimulus for intracoronary formation of leukotrienes (LTs). 2 Derived from arachidonic acid though the 5-lipoxygenase (5-LO) pathway, LTs are potent inflammatory mediators implicated in several pathophysiological processes associated with atherosclerosis. 3 Furthermore, the polymorphisms within the gene encoding the 5-LO activating protein (FLAP), which have been associated with an increased risk of myocardial infarction and stroke, 4 were recently reproduced in restenosis patients. 5 In the latter study, 2 of the FLAP gene polymorphisms studied were independent prognostic factors in predicting in-stent restenosis 6 months after PCI. 5

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“…Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of complex human diseases, most particularly asthma. Several genetic linkage and associations studies as well as gene expression studies have shown an association of the leukotriene biosynthesis pathway to CAD (Dwyer et al, 2004, Helgadottir et al, 2004, 2005b,a, Lohmussaar et al, 2005, Shah et al, 2008. Helgadottir et al (2004) identified a four-SNP haplotype (HapA) spanning the ALOX5AP gene that conferred a nearly two times greater risk of MI and stroke in a case-control cohort.…”

Section: Introductionmentioning

confidence: 99%

Assessment of LD Matrix Measures for the Analysis of Biological Pathway Association

Crosslin¹,

Qin²,

Hauser³

2010

Statistical Applications in Genetics and Molecular Biology

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Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression . To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis).In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r = 0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.

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ALOX5AP variants are associated with in-stent restenosis after percutaneous coronary intervention

Cited by 20 publications

References 25 publications

ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation

ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation

Leukotriene Receptor Antagonism and the Prevention of Extracellular Matrix Degradation During Atherosclerosis and In-Stent Stenosis

Assessment of LD Matrix Measures for the Analysis of Biological Pathway Association

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