title: Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents.
abstract: Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian models. We identified two humans homozygous for loss-of-function mutations in GALNT2 who demonstrated low HDL-C. We also found that GALNT2 loss of function in mice, rats, and nonhuman primates decreased HDL-C. O-glycoproteomics studies of a human GALNT2-deficient subject validated ANGPTL3 and ApoC-III as GalNAc-T2 targets. Additional glycoproteomics in rodents identified targets influencing HDL-C, including phospholipid transfer protein (PLTP). GALNT2 deficiency reduced plasma PLTP activity in humans and rodents, and in mice this was rescued by reconstitution of hepatic Galnt2. We also found that GALNT2 GWAS SNPs associated with reduced HDL-C also correlate with lower hepatic GALNT2 expression. These results posit GALNT2 as a direct modulator of HDL metabolism across mammals.
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Sumeet A
authors: SA
authors: Khetarpal
authors: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Institute of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark. Electronic address: schjoldager@sund.ku.dk.
authors: Katrine T
authors: KT
authors: Schjoldager
authors: Department of Clinical Biochemistry, Rigshospitalet and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors: Christina
authors: C
authors: Christoffersen
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Avanthi
authors: A
authors: Raghavan
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Andrew C
authors: AC
authors: Edmondson
authors: Institute of Human Genetics, University of Bonn, Bonn 53012, Germany; Department of Neonatology and Pediatric Intensive Care, University of Bonn, Bonn 53012, Germany.
authors: Heiko M
authors: HM
authors: Reutter
authors: Research Team on Neurodegenerative Diseases, Medical School and Pharmacy, Mohammed V University, 10100 Rabat, Morocco.
authors: Bouhouche
authors: B
authors: Ahmed
authors: Neurophysiology Division, Hospital of Specialities, CHIS Ibn Sina, 6402 Rabat, Morocco.
authors: Reda
authors: R
authors: Ouazzani
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
authors: Gina M
authors: GM
authors: Peloso
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Cecilia
authors: C
authors: Vitali
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Wei
authors: W
authors: Zhao
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Amritha Varshini Hanasoge
authors: AV
authors: Somasundara
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: John S
authors: JS
authors: Millar
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: YoSon
authors: Y
authors: Park
authors: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors: Gayani
authors: G
authors: Fernando
authors: Department of Applied Genomics, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors: Valentin
authors: V
authors: Livanov
authors: Gacheon Cardiovascular Research Institute, Gachon University, 21565 Incheon, Korea.
authors: Seungbum
authors: S
authors: Choi
authors: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, and AP-HP, Department of Genetics, Pitié-La Salpêtrière Hospital, 75013 Paris, France.
authors: Eric
authors: E
authors: Noé
authors: Department of Applied Genomics, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors: Pritesh
authors: P
authors: Patel
authors: Department of Applied Genomics, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors: Siew Peng
authors: SP
authors: Ho
authors: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
authors: Todd G
authors: TG
authors: Kirchgessner
authors: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Institute of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors: Hans H
authors: HH
authors: Wandall
authors: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Institute of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors: Lars
authors: L
authors: Hansen
authors: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Institute of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors: Eric P
authors: EP
authors: Bennett
authors: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Institute of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors: Sergey Y
authors: SY
authors: Vakhrushev
authors: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN Cambridge, UK; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Centre for Non-Communicable Diseases, 75300 Karachi, Pakistan.
authors: Danish
authors: D
authors: Saleheen
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors: Sekar
authors: S
authors: Kathiresan
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Christopher D
authors: CD
authors: Brown
authors: Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 04103 Leipzig, Germany; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
authors: Rami
authors: R
authors: Abou Jamra
authors: Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, and AP-HP, Department of Genetics, Pitié-La Salpêtrière Hospital, 75013 Paris, France.
authors: Eric
authors: E
authors: LeGuern
authors: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Institute of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
authors: Henrik
authors: H
authors: Clausen
authors: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rader@mail.med.upenn.edu.
authors: Daniel J
authors: DJ
authors: Rader
mesh_terms: D000595:Amino Acid Sequence; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D008076:Cholesterol, HDL / Q000097:blood; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D017350:N-Acetylgalactosaminyltransferases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D049294:Phospholipid Transfer Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011323:Primates; D040901:Proteomics; D051381:Rats; D014280:Triglycerides / Q000378:metabolism; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D008076:Cholesterol, HDL; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D017350:N-Acetylgalactosaminyltransferases; D049294:Phospholipid Transfer Proteins; D014280:Triglycerides; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C479896:ANGPTL3 protein, human