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

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-CIII_0a), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII_0c, 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-CIII_0a. This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII_0a 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.

Keywords: apolipoprotein C-III; diabetes mellitus type 2; genome-wide association study; glycomics; hypertriglyceridemia.

Figure 1

Manhattan and QQ plot of apo-CIII_0a genome-wide association study (GWAS). GWAS of apo-CIII_0a showing associations with alleles at the GALNT2 locus on chromosome 1. Manhattan plot (a) showing significance of the association of each single nucleotide polymorphism (SNP) allele with apo-CIII_0a by plotting the -log10 of the p-Value against the genomic position. The horizontal red dotted line corresponds to the genome-wide significance threshold of p = 5 × 10⁻⁸. Quantile–quantile plot (b) is a plot of the observed -log₁₀(p) against the expected -log₁₀(p) under the null hypothesis of no association. Deviation above the red dotted y = x line indicates lower p-Values that would be expected to occur by chance and implies statistically significant association.