期刊
ATHEROSCLEROSIS
卷 222, 期 1, 页码 154-157出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2012.02.012
关键词
Lipids; Cholesterol; siRNA; Atherosclerosis; Apolipoprotein B
资金
- Merck Sharp Dohme Corp
Objective: Genome-wide association studies (GWAS) are useful in studying the complex pathways underlying diseases such as atherosclerosis; however, additional testing is often necessary to identify the disease causal genes linked to GWAS loci. We used siRNA-mediated gene knockdown in primary human hepatocytes (PHuH) to identify potential GWAS causal genes affecting the hepatic secretion of apolipoprotein B (ApoB), ApoA1, and proprotein convertase subtilisin/kexin type 9. Materials and methods: Candidate causal genes within GWAS loci affecting human plasma levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were identified from the literature; 191 genes were selected from 74 loci. A functional siRNA screen was performed using PHuH. Results: Four genes: poly (ADP-ribose) polymerases member 10, haptoglobin, fucosyltransferase 1, and lysophosphatidic acid receptor 2 were identified and confirmed. Knocking down these genes reduced cell-associated and secreted ApoB levels. Conclusion: Modification of these four genes may affect plasma lipids through modulation of ApoB secretion. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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