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

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-CIII 1 and apo-CIII 2 ). 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-CIII 2 and with hypertriglyceridemia. In line, apo-CIII 2 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.