A study into rare GPR146 gene variants in humans and mice

Background and aims

G-protein coupled receptor 146 (GPR146)-deficient mice exhibit a moderate 21 % reduction in plasma cholesterol. This is associated with decreased phosphorylation of ERK1/2 and reduced SREBP2 activity in the liver, which leads to lower VLDL secretion. Insight into the role of GPR146 in humans is however limited. We therefore set out to study rare genetic variants in GPR146 to improve our understanding of this new player in lipid metabolism.

Methods

We used whole genome sequencing data from UK Biobank participants to search for rare coding variants in GPR146. We first carried out gene-based burden tests (using SAIGE-GENE-framework) and examined the association of individual variants with plasma cholesterol levels. One of the variants (P62L) was also studied using the Global Lipids Genetics Consortium (GLGC) data set and in a knock-in mouse model.

Results

We found that the combination of rare genetic variants identified in GPR146 is significantly associated with plasma cholesterol levels. Three rare variants, i.e. P62L, I129I, and A175T were individually associated with reduced plasma cholesterol. In the GLGC cohort, the P62L variant was associated with reductions in both HDL and LDL cholesterol. Follow-up experiments show lower plasma cholesterol levels in GPR146^P61L male and female mice (−13 %, p < 0.05 and −15 %, p < 0.005, respectively) when compared to controls due to a reduction in HDL cholesterol. The GPR146^P61L mice did not exhibit a change in VLDL secretion. In line, the ERK1/2 signalling pathway and Srebp2 mRNA expression in liver homogenates, and the secretion of apoB by primary hepatocytes of GPR146^P61L and wild-type mice were unchanged.

Conclusions

This study shows that rare GPR146 gene variants are associated with lower plasma cholesterol levels in humans. One of these variants, P62L is associated with reductions of HDL cholesterol and LDL cholesterol in humans while the ortholog in mice confers a loss of GPR146 function leading to only reduced HDL cholesterol. How GPR146 affects HDL metabolism in humans and mice remains to be resolved.