Identification of genes affecting apolipoprotein B secretion following siRNA-mediated gene knockdown in primary human hepatocytes

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• 作者：Xun Shen^a ; Wei Wang^b ; Liangsu Wang^a ; Caroline Houde^a ; Weizhen Wu^a ; Matt Tudor^c ; John R. Thompson^b ; Christine McCrary Sisk^d ; Brian Hubbard^a ; Jing Li^a ; ^c ; ^{jing_li4@merck.com}
• 关键词：Lipids ; Cholesterol ; siRNA ; Atherosclerosis ; Apolipoprotein B
• 刊名：Atherosclerosis
• 出版年：2012
• 期刊代码：28_00219150
• 类别：med
• 出版时间：May, 2012
• 卷：222
• 期：1
• 页码：154-157
• 文件大小：514 K

摘要

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.