Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents

Cell Metab. 2016 Aug 9;24(2):234-45. doi: 10.1016/j.cmet.2016.07.012.

Sumeet A Khetarpal ¹, Katrine T Schjoldager ², Christina Christoffersen ³, Avanthi Raghavan ¹, Andrew C Edmondson ¹, Heiko M Reutter ⁴, Bouhouche Ahmed ⁵, Reda Ouazzani ⁶, Gina M Peloso ⁷, Cecilia Vitali ¹, Wei Zhao ¹, Amritha Varshini Hanasoge Somasundara ¹, John S Millar ¹, YoSon Park ⁸, Gayani Fernando ⁹, Valentin Livanov ¹⁰, Seungbum Choi ¹¹, Eric Noé ¹², Pritesh Patel ¹⁰, Siew Peng Ho ¹⁰, Myocardial Infarction Exome Sequencing Study, Todd G Kirchgessner ⁹, Hans H Wandall ¹³, Lars Hansen ¹³, Eric P Bennett ¹³, Sergey Y Vakhrushev ¹³, Danish Saleheen ¹⁴, Sekar Kathiresan ¹⁵, Christopher D Brown ⁸, Rami Abou Jamra ¹⁶, Eric LeGuern ¹², Henrik Clausen ¹³, Daniel J Rader ¹⁷

Affiliations

1 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.
2 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.
3 Department of Clinical Biochemistry, Rigshospitalet and Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
4 Institute of Human Genetics, University of Bonn, Bonn 53012, Germany; Department of Neonatology and Pediatric Intensive Care, University of Bonn, Bonn 53012, Germany.
5 Research Team on Neurodegenerative Diseases, Medical School and Pharmacy, Mohammed V University, 10100 Rabat, Morocco.
6 Neurophysiology Division, Hospital of Specialities, CHIS Ibn Sina, 6402 Rabat, Morocco.
7 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.
8 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
9 Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
10 Department of Applied Genomics, Bristol-Myers Squibb, Pennington, NJ 08534, USA.
11 Gacheon Cardiovascular Research Institute, Gachon University, 21565 Incheon, Korea.
12 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.
13 Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine and Odontology, Institute of Health Sciences, University of Copenhagen, Blegdamsvej 3, Copenhagen 2200, Denmark.
14 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.
15 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.
16 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.
17 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.

PMID: 27508872 DOI: 10.1016/j.cmet.2016.07.012

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.

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