title: Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans.
abstract: While genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with large effects in candidate genes contributing to extreme HDLc in humans, utilizing family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with extremely low (≤10th percentile) or high (≥90th percentile) HDLc. Probands were excluded if known mutations existed in the established HDLc-regulating genes ABCA1, APOA1, LCAT, cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2). We identified 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped in the proband's family. Family-based association analyses were performed for variants with sufficient power to detect significance at P < 0.05 with a total of 627 family members being assessed. Mutations in the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor 3 (LILRA3), and dynein axonemal heavy chain 10 (DNAH10) segregated with elevated HDLc levels in families, while no mutations associated with low HDLc. Taken together, we have identified mutations in four novel genes that may play a role in regulating HDLc levels in humans.
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada A*STAR Institute and Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Tietjen
authors.affiliation: Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Franchini
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Radomski
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Kenny
authors.initials: K
authors.lastname: Wong
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Margaret
authors.initials: M
authors.lastname: vanHeek
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Ioannis M
authors.initials: IM
authors.lastname: Stylianou
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Linus
authors.initials: L
authors.lastname: Lin
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Liangsu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Lyndon
authors.initials: L
authors.lastname: Mitnaul
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Winther
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Maryanne
authors.initials: M
authors.lastname: Mattice
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Annick
authors.initials: A
authors.lastname: Legendre
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Sherrington
authors.affiliation: Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Karen
authors.initials: K
authors.lastname: Akinsanya
authors.affiliation: Merck Research Laboratories, Rahway, NJ.
authors.forename: Andrew
authors.initials: A
authors.lastname: Plump
authors.affiliation: A*STAR Institute and Yong Loo Lin School of Medicine, National University of Singapore, Singapore Centre for Molecular Medicine and Therapeutics, and Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000235:genetics; D056444:Axonemal Dyneins / Q000235:genetics*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D004722:Endoribonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D008049:Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics*; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D064286:ATP Binding Cassette Transporter 1; D048868:Adaptor Proteins, Signal Transducing; D016632:Apolipoprotein A-I; D056444:Axonemal Dyneins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004722:Endoribonucleases; D008049:Lipase; D017350:N-Acetylgalactosaminyltransferases; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D011971:Receptors, Immunologic; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C577836:ABCA1 protein, human; C505693:APOA1 protein, human; C506642:CETP protein, human; C485100:GCKR protein, human; C530062:LILRA3 protein, human; C410382:LIPG protein, human; C031956:2-5A-dependent ribonuclease
keywords: Mendelian genetics; genetics; high density lipoprotein; high density lipoprotein metabolism; lipids; lipoproteins