title: Identification of genes affecting apolipoprotein B secretion following siRNA-mediated gene knockdown in primary human hepatocytes.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  Modification of these four genes may affect plasma lipids through modulation of ApoB secretion.
authors.affiliation: Cardiovascular Disease, Merck Sharp & Dohme Corp., Whitehouse Station, NJ 08889, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Shen
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
authors.forename: Caroline
authors.initials: C
authors.lastname: Houde
authors.forename: Weizhen
authors.initials: W
authors.lastname: Wu
authors.forename: Matt
authors.initials: M
authors.lastname: Tudor
authors.forename: John R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Christine McCrary
authors.initials: CM
authors.lastname: Sisk
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.forename: Jing
authors.initials: J
authors.lastname: Li
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005647:Fucosyltransferases / Q000235:genetics; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006242:Haptoglobins / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics; D012697:Serine Endopeptidases / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005647:Fucosyltransferases; D006242:Haptoglobins; D011065:Poly(ADP-ribose) Polymerases; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D049368:Receptors, Lysophosphatidic Acid; D012697:Serine Endopeptidases; D014280:Triglycerides; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C485359:HP protein, human; C499627:PARP10 protein, human; C472125:PCSK9 protein, human