Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids

Author:

Naber Annemieke1ORCID,Demus Daniel2,Slieker Roderick34,Nicolardi Simone2ORCID,Beulens Joline W. J.456,Elders Petra J. M.7,Lieverse Aloysius G.8,Sijbrands Eric J. G.1,’t Hart Leen M.3459ORCID,Wuhrer Manfred2ORCID,van Hoek Mandy1

Affiliation:

1. Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands

2. Center for Proteomics and Metabolomics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands

3. Department of Cell and Chemical Biology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands

4. Department of Epidemiology and Data Science, Amsterdam UMC, Location Vrije Universiteit Amsterdam, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

5. Amsterdam Public Health, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

6. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands

7. Department of General Practice, Amsterdam Public Health Institute, Amsterdam UMC, Location VUmc, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

8. Department of Internal Medicine, Maxima Medical Center, P.O. Box 90052, 5600 PD Eindhoven, The Netherlands

9. Department of Biomedical Data Science, Section Molecular Epidemiology, Leiden University Medical Center, Postal Zone S5-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands

Abstract

Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII0a), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII0c, apo-CIII1 and apo-CIII2). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation. We conducted GWAS on the four apo-CIII proteoforms in the DiaGene study in people with and without type 2 diabetes (n = 2318). We investigated the relations of the identified genetic loci and apo-CIII glycosylation with lipids and type 2 diabetes. The associations of the genetic variants with lipids were replicated in the Diabetes Care System (n = 5409). Rs4846913-A, in the GALNT2-gene, was associated with decreased apo-CIII0a. This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII0a was associated with raised high-density lipoprotein-cholesterol and triglycerides. Rs67086575-G, located in the IFT172-gene, was associated with decreased apo-CIII2 and with hypertriglyceridemia. In line, apo-CIII2 was associated with low triglycerides. On a genome-wide scale, we confirmed that the GALNT2-gene plays a major role i O-glycosylation of apolipoprotein-CIII, with subsequent associations with lipid parameters. We newly identified the IFT172/NRBP1 region, in the literature previously associated with hypertriglyceridemia, as involved in apolipoprotein-CIII sialylation and hypertriglyceridemia. These results link genomics, glycosylation, and lipid metabolism, and represent a key step towards unravelling the importance of O-glycosylation in health and disease.

Funder

European Union’s Horizon 2020 research and innovation programme

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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