Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction

Knowles, Joshua; Wang, Huijan; Itakura, Haruka; Southwick, Audrey; Myers, R; Iribarren, Carlos; Fortmann, Stephen P.; Go, Alan S.; Quertermous, Thomas; Hlatky, Mark A.

doi:10.1016/j.ahj.2007.05.021

Cited by 44 publications

(34 citation statements)

References 49 publications

(21 reference statements)

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“…Although there has been some controversy about the contribution of CD36 to atherogenesis (29), studies of several murine in vivo model systems, including high fat diet-stressed apoE Ϫ/Ϫ and LDLR Ϫ/Ϫ strains crossed into at least two CD36 Ϫ/Ϫ strains, as well as studies of CD36 Ϫ/Ϫ bone marrow chimeras and CD36 inhibitor-treated mice have shown dramatically smaller plaque lesions and/or less complex lesions with less aortic cholesterol in the absence of functional CD36 (5-8, 30, 31). Importantly, recent genome-wide association studies in humans suggest a link between CD36 polymorphisms and myocardial infarction, further supporting this hypothesis (32).…”

Section: Discussionsupporting

confidence: 55%

Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

Rahaman¹,

Swat

Febbraio

et al. 2011

Journal of Biological Chemistry

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Lipid-laden macrophages or "foam cells" are the primary components of the fatty streak, the earliest atherosclerotic lesion. Although Vav family guanine nucleotide exchange factors impact processes highly relevant to atherogenesis and are involved in pathways common to scavenger receptor CD36 signaling, their role in CD36-dependent macrophage foam cell formation remains unknown. The goal of the present study was to determine the contribution of Vav proteins to CD36-dependent foam cell formation and to identify the mechanisms by which Vavs participate in the process. We found that CD36 contributes to activation of Vav-1, -2, and -3 in aortae from hyperlipidemic mice and that oxidatively modified LDL (oxLDL) induces activation of macrophage Vav in vitro in a CD36 and Src family kinase-dependent manner. CD36-dependent uptake of oxLDL in vitro and foam cell formation in vitro and in vivo was significantly reduced in Vav null macrophages. These studies for the first time link CD36 and Vavs in a signaling pathway required for macrophage foam cell formation.Atherosclerosis is a complex inflammatory process driven in part by macrophage uptake of oxidized low density lipoproteins (oxLDL) 4 by scavenger receptors, such as CD36 and scavenger receptor A (1), leading to formation of lipid-laden "foam cells," the primary component of the earliest atherosclerotic lesions. Studies from our group and others demonstrated that CD36 accounts for a large proportion of foam cell formation in vitro and in vivo and that interruption of CD36 expression or downstream signaling blocks oxLDL uptake and limits experimental atherosclerosis in mice (2-9). CD36 is a multifunctional, multiligand transmembrane receptor expressed in a diverse array of cells including monocytes/macrophages, platelets, and adipocytes. Interestingly, CD36 deficiency is found in 0.5-1.0% of African and Asian populations (10, 11), and although atherosclerosis has yet to be studied in these groups, monocyte-derived macrophages collected from CD36-null individuals demonstrated 40% less binding and uptake of oxLDL compared with control individuals (12) with significant impairment of oxLDL-induced activation of NF-B and expression of proinflammatory genes (13). Numerous studies have revealed that CD36 acts as a signaling receptor, transmitting signals via Src family kinases (SFK) Lyn and Fyn, and MAP kinases JNK and p38, in response to multiple endogenous and exogenous ligands, including microbial pathogens, oxLDL, apoptotic cells, cell-derived microparticles, thrombospondin-related proteins, and amyloid peptides (14 -16). The precise molecular details, however, by which ligation of CD36 leads to recruitment and activation of a signaling complex are not fully understood. Identification of intracellular pathways required for oxLDL uptake and foam cell formation is vital for understanding the initiating stages of atherosclerosis and for designing novel targeted inhibitory agents. The studies outlined here demonstrate a critical role for Vav proteins in mediating CD36-depe...

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Section: Discussionsupporting

confidence: 55%

Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

Rahaman¹,

Swat

Febbraio

et al. 2011

Journal of Biological Chemistry

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“…However, the extent of the contribution of genetic risk factors to this prevalence remains unstudied. We developed a cross-sectional study of risk factors for AT, including characterization of the polymorphisms in a series of established susceptibility genes for AT, namely ACE-angiotensin converting enzyme (Rigat et al 1990;Samani et al 1996;Sabbagh et al 2007), PAI1-plasminogen activator inhibitor 1 (Onalan et al 2008), NOS3-nitric oxide synthase (Casas et al 2004), LTA-lymphotoxin a (Schreyer et al 2002;Trompet et al 2008), FGB-fibrinogen b (Renner et al 2002;Gialeraki et al 2008), ITGB3-integrin b-3 (Marian et al 1996;Ridker et al 1997;Knowles et al 2007), PON1-paraoxonase 1 (Mackness et al 1998;Salonen et al 1999;Garcés et al 2008) and APOE-apolipoprotein E (Burman et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Cross-sectional study of risk factors for atherosclerosis in the Azorean population

Cymbron

Raposo

Kazachkova

et al. 2011

Annals of Human Biology

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Background: Atherosclerosis-a major cause of vascular disease, including ischemic heart disease (IHD), is a pathology that has a two-fold higher mortality rate in the Azorean Islands compared to mainland Portugal. Aim: This cross-sectional study investigated the role of genetic variation in the prevalence of atherosclerosis in this population. Subjects and methods: A total of 305 individuals were characterized for polymorphisms in eight susceptibility genes for atherosclerosis: ACE, PAI1, NOS3, LTA, FGB, ITGB3, PON1 and APOE. Data were analysed with respect to phenotypic characteristics such as blood pressure, lipid profile, life-style risk factors and familial history of myocardial infarction. Results: In the total sample, frequencies for hypercholestrolemic, hypertensive and obese individuals were 63.6%, 39.3% and 23.3%, respectively. The genetic profile was similar to that observed in other European populations, namely in mainland Portugal. No over-representation of risk alleles was evidenced in this sample. Conclusions: One has to consider the possibility of an important non-genetic influence on the high cholesterolemia present in the Azorean population. Since diet is the most important life-style risk factor for dyslipidemia, studies aiming to evaluate the dietary characteristics of this population and its impact on serum lipid levels will be of major importance.

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“…[21][22][23][24][25][26] SNPs in other genes from these pathways modulate CHD risk, presumably through their effects on lipids. [27][28][29][30][31] Thus, inclusion of these genes among enriched gene sets is supported by existing scientific literature.…”

Section: Discussionmentioning

confidence: 75%

Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets

Fuentes¹,

Yang

Dávila‐Román³

et al. 2012

Eur J Hum Genet

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Genome-wide association (GWA) studies of complex diseases including coronary heart disease (CHD) challenge investigators attempting to identify relevant genetic variants among hundreds of thousands of markers being tested. A selection strategy based purely on statistical significance will result in many false negative findings after adjustment for multiple testing. Thus, an integrated analysis using information from the learned genetic pathways, molecular functions, and biological processes is desirable. In this study, we applied a customized method, variable set enrichment analysis (VSEA), to the Framingham Heart Study data (404 467 variants, n ¼ 6421) to evaluate enrichment of genetic association in 1395 gene sets for their contribution to CHD. We identified 25 gene sets with nominal Po0.01; at least four sets are previously known for their roles in CHD: vascular genesis (GO:0001570), fatty-acid biosynthetic process (GO:0006633), fatty-acid metabolic process (GO:0006631), and glycerolipid metabolic process (GO:0046486). Although the four gene sets include 170 genes, only three of the genes contain a variant ranked among the top 100 in single-variant association tests of the 404 467 variants tested. Significant enrichment for novel gene sets less known for their importance to CHD were also identified: Rac 1 cell-motility signaling pathway (h_rac1 Pathway, Po0.001) and sulfur amino-acid metabolic process (GO:0000096, Po0.001). In summary, we showed that the pathway-based VSEA can help prioritize association signals in GWA studies by identifying biologically plausible targets for downstream searches of genetic variants associated with CHD.

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Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction

Abstract: Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.

Cited by 44 publications

References 49 publications

Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

Cross-sectional study of risk factors for atherosclerosis in the Azorean population

Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets

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