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

Sumeet A Khetarpal; Katrine T Schjoldager; Christina Christoffersen; 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; Hans H Wandall; Lars Hansen; Eric P Bennett; Sergey Y Vakhrushev; Danish Saleheen; Sekar Kathiresan; Christopher D Brown; Rami Abou Jamra; Eric LeGuern; Henrik Clausen; Daniel J Rader

doi:10.1016/j.cmet.2016.07.012

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

Sumeet A Khetarpal, Katrine T Schjoldager, Christina Christoffersen, 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 HoTodd G Kirchgessner, Hans H Wandall, Lars Hansen, Eric P Bennett, Sergey Y Vakhrushev, Danish Saleheen, Sekar Kathiresan, Christopher D Brown, Rami Abou Jamra, Eric LeGuern, Henrik Clausen, Daniel J Rader

66 Citations (Scopus)

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.

Original language	English
Journal	Cell Metabolism
Volume	24
Issue number	2
Pages (from-to)	234-245
Number of pages	12
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2016.07.012
Publication status	Published - 9 Aug 2016

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Khetarpal, S. A., Schjoldager, K. T., Christoffersen, C., Raghavan, A., Edmondson, A. C., Reutter, H. M., Ahmed, B., Ouazzani, R., Peloso, G. M., Vitali, C., Zhao, W., Somasundara, A. V. H., Millar, J. S., Park, Y., Fernando, G., Livanov, V., Choi, S., Noé, E., Patel, P., ... Rader, D. J. (2016). Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents. Cell Metabolism, 24(2), 234-245. https://doi.org/10.1016/j.cmet.2016.07.012

Khetarpal, SA, Schjoldager, KT , Christoffersen, C, Raghavan, A, Edmondson, AC, Reutter, HM, Ahmed, B, Ouazzani, R, Peloso, GM, Vitali, C, Zhao, W, Somasundara, AVH, Millar, JS, Park, Y, Fernando, G, Livanov, V, Choi, S, Noé, E, Patel, P, Ho, SP, Kirchgessner, TG, Wandall, HH , Hansen, L , Bennett, EP , Vakhrushev, SY, Saleheen, D, Kathiresan, S, Brown, CD, Abou Jamra, R, LeGuern, E, Clausen, H & Rader, DJ 2016, 'Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents', Cell Metabolism, vol. 24, no. 2, pp. 234-245. https://doi.org/10.1016/j.cmet.2016.07.012

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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.",

author = "Khetarpal, {Sumeet A} and Schjoldager, {Katrine T} and Christina Christoffersen and Avanthi Raghavan and Edmondson, {Andrew C} and Reutter, {Heiko M} and Bouhouche Ahmed and Reda Ouazzani and Peloso, {Gina M} and Cecilia Vitali and Wei Zhao and Somasundara, {Amritha Varshini Hanasoge} and Millar, {John S} and YoSon Park and Gayani Fernando and Valentin Livanov and Seungbum Choi and Eric No{\'e} and Pritesh Patel and Ho, {Siew Peng} and Kirchgessner, {Todd G} and Wandall, {Hans H} and Lars Hansen and Bennett, {Eric P} and Vakhrushev, {Sergey Y} and Danish Saleheen and Sekar Kathiresan and Brown, {Christopher D} and {Abou Jamra}, Rami and Eric LeGuern and Henrik Clausen and Rader, {Daniel J}",

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T1 - Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents

AU - Khetarpal, Sumeet A

AU - Schjoldager, Katrine T

AU - Christoffersen, Christina

AU - Raghavan, Avanthi

AU - Edmondson, Andrew C

AU - Reutter, Heiko M

AU - Ahmed, Bouhouche

AU - Ouazzani, Reda

AU - Peloso, Gina M

AU - Vitali, Cecilia

AU - Zhao, Wei

AU - Somasundara, Amritha Varshini Hanasoge

AU - Millar, John S

AU - Park, YoSon

AU - Fernando, Gayani

AU - Livanov, Valentin

AU - Choi, Seungbum

AU - Noé, Eric

AU - Patel, Pritesh

AU - Ho, Siew Peng

AU - Kirchgessner, Todd G

AU - Wandall, Hans H

AU - Hansen, Lars

AU - Bennett, Eric P

AU - Vakhrushev, Sergey Y

AU - Saleheen, Danish

AU - Kathiresan, Sekar

AU - Brown, Christopher D

AU - Abou Jamra, Rami

AU - LeGuern, Eric

AU - Clausen, Henrik

AU - Rader, Daniel J

PY - 2016/8/9

Y1 - 2016/8/9

N2 - 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.

AB - 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.

U2 - 10.1016/j.cmet.2016.07.012

DO - 10.1016/j.cmet.2016.07.012

M3 - Journal article

C2 - 27508872

SN - 1550-4131

VL - 24

SP - 234

EP - 245

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

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

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