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

Research output: Contribution to journalJournal article

  • Sumeet A Khetarpal
  • Avanthi Raghavan
  • Andrew C Edmondson
  • Heiko M Reutter
  • Bouhouche Ahmed
  • Reda Ouazzani
  • Gina M Peloso
  • Cecilia Vitali
  • Wei Zhao
  • Amritha Varshini Hanasoge Somasundara
  • John S Millar
  • YoSon Park
  • Gayani Fernando
  • Valentin Livanov
  • Seungbum Choi
  • Eric Noé
  • Pritesh Patel
  • Siew Peng Ho
  • Todd G Kirchgessner
  • Danish Saleheen
  • Sekar Kathiresan
  • Christopher D Brown
  • Rami Abou Jamra
  • Eric LeGuern
  • Daniel J Rader
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.
Original languageEnglish
JournalCell Metabolism
Volume24
Issue number2
Pages (from-to)234-245
Number of pages12
ISSN1550-4131
DOIs
Publication statusPublished - 9 Aug 2016

ID: 166272748