Previous studies show that GALNT2 was among the first novel genes associated with HDL-C and triglycerides, for blood lipid traits. Despite the early implication of the GALNT2 locus, the specific role of this gene in HDL-C levels remained elusive. GWAS has identified many new areas of the genome as novel and potentially important contributors to disease-related traits like lipid levels, however, finding the specific genes in these regions and how they affect these traits has been very challenging. The current study provides one blueprint for how to relate a GWAS-implicated gene to a clinically relevant phenotype across species.
The current study identifies two humans carrying variants in GALNT2 in two independent families that both completely blocked the gene’s enzymatic function. The lab compared the HDL-C levels of the carriers of these variants to mouse, rat, and monkey models of GALNT2 deficiency or inhibition, to show that all the models and the human subjects had low HDL levels compared to models with GALNT2.
The group state that they also sought to understand how GALNT2 maintains HDL-C levels, as the gene encodes enzyme modifying proteins through carbohydrate additions. Therefore, they compared all the proteins in the blood and liver, a tissue critical to regulating HDL levels, in the humans, mice and rats with GALNT2 deficiency to pinpoint any proteins with reduced modifications that may impact HDL levels. Results show that humans, mice, and rats lacking GALNT2 had reduced activity of phospholipid transfer protein (PLTP) in the blood, which suggests that GALNT2 is a conserved regulator of HDL levels through its effects on PLTP function.