Progression of Atherosclerosis Is Associated With Variation in the α
            <sub>1</sub>
            -Antitrypsin Gene

Talmud, Philippa J.; Martin, Spencer D.; Steiner, George; Flavell, David M.; Whitehouse, David; Nagl, Sylvia; Jackson, Richard M.; Taskinen, Marja‐Riitta; Frick, M. H.; Nieminen, Markku S.; Ya, Kesäniemi; Pasternack, Amos; Humphries, Steve E.; Syvänne, Mikko

doi:10.1161/01.atv.0000065196.61663.8d

Cited by 69 publications

(53 citation statements)

References 27 publications

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“…This observation suggests that endogenous levels of AAT prevent infection of HIV-1. In fact, adding exogenous human AAT to latently-infected cell lines reduced production of HIV-1 in vitro (49). Thus, steady-state levels of AAT appear to provide a certain degree of HIV-1 infection inhibition.…”

Section: Binding Targets That Are Unrelated To Protease Inhibitionmentioning

confidence: 97%

“…In addition, studies point at a direct relationship between AAT and apolipoprotein B on LDL particles (47,48), and AAT-LDL complexes have been detected in human atherosclerotic lesions (48). In support of a therapeutic implication for such an association, a protective role for AAT in atherosclerosis was demonstrated in the Lipid Coronary Angiography Trial that evaluated male participants after coronary bypass surgery (49); the authors of the trial concluded that low AAT levels are associated with increased occurrence of atherogenesis.…”

Section: Binding Targets That Are Unrelated To Protease Inhibitionmentioning

confidence: 99%

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Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

146

115

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α 1 -Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/mL circulating levels. During acute-phase responses, circulating AAT levels increase more than fourfold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema. These individuals are treated with lifelong weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3 (PR-3), but also to exert antiinflammatory and tissue-protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undeterred isolated T-lymphocyte responses. On the basis of preclinical and clinical studies, AAT therapy for nondeficient individuals may interfere with disease progression in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and human immunodeficiency virus (HIV), and is currently evaluated in clinical trials for type 1 diabetes, cystic fibrosis and graft versus host disease. Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.

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Section: Binding Targets That Are Unrelated To Protease Inhibitionmentioning

confidence: 97%

Section: Binding Targets That Are Unrelated To Protease Inhibitionmentioning

confidence: 99%

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

146

115

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“…To date, variations in the peroxisome proliferator-activated receptor ␣ gene, PPARA L162V and intron 7G Ͼ C (14), the stromelysin gene, MMP3 5A/6A (15), the platelet endothelial cell adhesion molecule-1 gene, PECAM1 53G Ͼ A (16), and the ␣ -1-antitrypsin gene, AAT V213A and 11478G Ͼ A (17), have all shown significant associations with the progression of atherosclerosis in LOCAT, with AAT V213A showing a pharmacogenetic interaction with the response to gemfibrozil treatment. In contrast, variation in the hepatic lipase (HL) gene LIPC Ϫ 514C Ͼ T, although showing strong association with HL activity and lipid parameters, showed no association with atherosclerosis progression (18).…”

mentioning

confidence: 99%

APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease

Talmud

Martin

Taskinen

et al. 2004

Journal of Lipid Research

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100

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Animal and human studies of the newly identified APOA5 gene are consistent in identifying APOA5 as a major determinant of plasma triglyceride (TG) levels (1). Thus, APOA5 , forming a cluster with APOA4-C3-A1 on chromosome 11q23, constitutes a locus involved in TG and HDL determination (2, 3). In both transgenic and knockout mouse models, it is clear that apolipoprotein A-V (apoA-V) is inversely associated with plasma TG levels. Transgenic mice overexpressing human APOA5 (1) or adenoviral vector-mediated transfer of APOA5 into mice (4) produce a 60-70% decrease in TG, whereas apoA5 knockout mice have 4-fold higher plasma TG than controls (1). The human APOA5 gene is fairly polymorphic, and in Caucasians, three common haplotypes have been identified: wild-type haplotype APOA5 * 1; APOA5 * 2, defined by rare alleles of Ϫ 1131T Ͼ C, c-3A Ͼ G, IVS3 ϩ 476G Ͼ T, and c1259T Ͼ C; and APOA5 * 3, defined by a rare allele of S19W (5) and thus genotyping for Ϫ 1131T Ͼ C or S19W, essentially acting as tagging single nucleotide polymorphisms (SNPs) (6). The Ϫ 1131C variants and to a lesser extent 19W have been associated with increased TG in healthy Caucasians (1, 5, 7-9) and in African Americans and Hispanics (5) and with higher relative risk of developing dyslipidemias (10, 11). The rare allele of Ϫ 1131T Ͼ C is more common in Japanese compared with Caucasians (0.34 versus 0.08, respectively) (12) and shows a strong association with TG levels, even in young school-age children. However, despite these consistent associations with TG levels, the function and role of apoA-V in TG metabolism remains unclear.To examine the relationship between APOA5 gene variants and the metabolism of TG-rich particles in more

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“…Inhibition of A1AT uptake by cigarette smoke may further weaken the A1AT protective role in the lung. In the last decade other physiological roles of A1AT have been discovered, such as roles in atherogenesis (Talmud et al, 2003), angiogenesis (Huang et al, 2004), fibroblast proliferation, and procollagen synthesis (Dabbagh et al, 2001). …”

Section: Physiological Roles Of Alpha-1-antitrypsinmentioning

confidence: 99%

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

Topić¹,

Radojković²

2012

Lung Diseases - Selected State of the Art Reviews

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Progression of Atherosclerosis Is Associated With Variation in the α ₁ -Antitrypsin Gene

Abstract: Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis.

Cited by 69 publications

References 27 publications

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Expanding the Clinical Indications for α1-Antitrypsin Therapy

APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

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Progression of Atherosclerosis Is Associated With Variation in the α 1 -Antitrypsin Gene

Abstract: Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis.

Cited by 69 publications

References 27 publications

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Expanding the Clinical Indications for α1-Antitrypsin Therapy

APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease

Polymerization and Oxidation of Alpha-1-Antitrypsin in Pathogenesis of Emphysema

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Product

Resources

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Progression of Atherosclerosis Is Associated With Variation in the α ₁ -Antitrypsin Gene