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Title: The role of Serum Amyloid A1(SAA1) in coronary artery disease
Keywords: atherosclerosis, SAA1, acute-phase protein, coronary artery disease, HRM, Epidemiology study
Issue Date: 28-Feb-2011
Source: LEOW KOON YEOW (2011-02-28). The role of Serum Amyloid A1(SAA1) in coronary artery disease. ScholarBank@NUS Repository.
Abstract: Background: Atherosclerosis is a gradual narrowing of the lumen of the arteries and chronic inflammation has long being regarded as crucial to the pathogenesis of the disease. Serum amyloid A1 (SAA1) and serum amyloid A2 (SAA2) (A-SAA) are acute-phase proteins (APPs); the concentration of A-SAA can increase by 500-1000 fold during an acute systemic inflammation (Malle et al. 1993). The predominant form of A-SAA in plasma is reported to be SAA1 (Yamada et al. 1999). A-SAA has increasingly been associated with atherosclerosis (Johnson et al. 2004; Ogasawara et al. 2004; Ridker et al. 2000), this stem from its immune regulatory role as well as the inflammatory nature of atherosclerosis. However, its specific role in atherosclerosis, in particular, whether it is atherogenic or atheroprotective remains unknown. In addition, no prior genetic epidemiology study has been conducted on SAA1. Methods and results: Genetic variant screening was performed using cord blood DNA samples from 96 anonymous, unrelated Singaporean Chinese neonates delivered in the National University Hospital, Singapore. Genetic association study was performed using DNA samples extracted from blood samples belonging to coronary artery disease (CAD) patients. In total, there were 1243 healthy controls and 800 CAD patients. Healthy controls were recruited from subjects attending a routine health screening. Functional characterization of the genetic variant, p.Gly90Asp, was performed in vitro using human THP-1 derived macrophages. In total, 6 genetic variants were identified in the exons and promoter of SAA1, of which 2 are novel - c.-913G>A and c.92-5T>G. The non-conservative genetic variant, p.Gly90Asp (c.269G>A), is not associated with CAD, the odds ratio is 1.61 (95% confidence interval (CI) 0.68-3.80; P-value =0.28) after adjustment for age, gender and BMI. In addition, the variant, p.Gly90Asp also induced a significantly lower level of inflammatory cytokines in THP-1 derived macrophages, the decrease in IL-8, MCP-1 and TNF-a secreted were 57%, 50% and 39% respectively. Variant SAA1 also has a lower impact on the genetic expression level of a potentially atheroprotective gene, plasminogen activator inhibitor-2 precurosor (SERPINB2), the expression ratio of wild-type SAA1 to variant SAA1 is 1.8 (95% confidence interval (CI) 1.3-2.4; P-value < 0.0001). Microarray study also suggests an atherogenic role of SAA1 with the induction of genes that are involved in inflammation, angiogenesis, phagocytosis and tissue remodeling; these processes are crucial to the development of atherosclerotic lesion. Conclusions: The identification of a genetic mutant of SAA1, p.Gly90Asp that is associated with CAD supports the hypothesis that SAA1 has a direct role to play in the pathogenesis of CAD. p.Gly90Asp has altered functional effects and induces a lower extent of cytokine secretion in macrophages and potentially atheroprotective SERPINB2, the latter could account for the increased susceptibility of p.Gly90Asp to CAD. The alter effects of the mutant is probably due to the lower affinity of the genetic variant to cell surface receptors of SAA1 such as TLR2 and CLA-1. Lastly, SAA1 regulates expression of genes with functional roles in key processes of atherosclerosis; it thus plays a direct role in CAD and does not act as a mere marker of chronic inflammatory diseases.
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