Variant screening of the serum amyloid A1 gene and functional study of the p.Gly90Asp variant for its role in atherosclerosis

• Published in: Atherosclerosis Vol. 227; no. 1; pp. 112 - 117
• Main Authors: Leow, Koon-Yeow, Goh, Wilson Wen Bin, Tan, Si-Zhen, Lim, Jimmy, Ng, Kenneth, Oh, Vernon Min-Sen, Low, Adrian Fatt-Hoe, Heng, Chew-Kiat
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01.03.2013
• Subjects: acute phase proteins; Acute-phase protein; alleles; amyloid; Asian Continental Ancestry Group - genetics; Asian People; Atherosclerosis; Atherosclerosis - genetics; blood serum; Cardiovascular; coronary artery disease; Coronary Artery Disease - genetics; exons; Gene Frequency; genetics; Humans; inflammation; interleukin-8; leukemia; macrophages; patients; Polymorphism, Single Nucleotide; SAA1; screening; secretion; Serum Amyloid A Protein; Serum Amyloid A Protein - genetics; tumor necrosis factor-alpha; SAA1; Acute-phase protein; Atherosclerosis
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2013.01.003

Serum amyloid A1 (SAA1) is a major acute-phase protein that is increasingly used as a reliable predictor of coronary artery disease (CAD). In this study we aim to screen the SAAI promoter and exons for genetic variants and to determine their association with CAD. In addition, we also carried out functional study on a variant of p.Gly90Asp encoded by the SAA1 gene. Variant screening of SAA1 was performed using high resolution melting (HRM) analysis. Genetic association of p.Gly90Asp with CAD was determined in 800 CAD patients and 773 Chinese control subjects. Functional study of p.Gly90Asp was carried out using THP-1-derived macrophages and HL-60 promyelocytic leukemia cells. A total of 6 SNPs were identified, of which 2 were found to be novel (c.-913G > A and c.92-5T > G). The rare allele of p.Gly90Asp has a lower frequency of 0.013 in the CAD patients although this is not statistically significant. Functional studies of p.Gly90Asp revealed that the variant has decreased upregulation of key cytokines such as IL-8, MCP-1 and TNF-α as well as SERPINB2. We found the variant p.Gly90Asp SAA1 protein eliciting significantly reduced inflammatory responses in macrophages through a reduction in the secretion of inflammatory cytokines. Despite strong functional effects, the minor allele frequency is too low in the population to attain statistical significance difference between cases and controls. ► First genetic association study of a rare SAA1 variant, p.Gly90Asp. ► First genetic variant screening of human SAA1, using the modern method of high resolution melting. ► Identification of downstream targets of SAA1 through the functional study of p.Gly90Asp.