191 - Rare GPR146 variants and their impact in the regulation of plasma lipid levels (ID 1011)
Abstract
Background and Aims
Recent studies indicate that Gpr146-/- mice exhibit decreased plasma lipid levels and atherosclerosis development, independently of the LDLR pathway. Here we aim to identify and characterize rare coding variants in the GPR146 gene, with loss-of-function (LOF) impact, to further evaluate whether GPR146 inhibition could be a promising novel lipid-lowering strategy in humans.
Methods
We sequenced the gene GPR146 in 513 individuals with LDL-c ≤2nd percentile and 967 individuals with LDL-c ≥98th percentile. Genetic variants found to be enriched in the low LDL-c group were further investigated in public sequencing data from the UK-Biobank for association with plasma lipid traits and the risk of myocardial infraction (MI). We further characterized the plasma metabolomics profile of this LOF variant carriers using the Nightingale platform.
Results
We show that one variant in GPR146 is enriched in the low LDL-c group when compare with high LDL-c group. The variant carriers present decreased levels of HDL-c, Total Cholesterol and LDL-c, without significant effect on triglycerides or risk of MI in UKBB. The refinement of metabolomics profiles shows a significant reductions HDL particle size in GPR146-LOF variant carriers.
Conclusions
We have identified a rare GPR146 variant predicted to have LOF effect based on human genetics. Our current findings on this variant do not support GPR146 inhibition to prevent atherosclerosis, but its lack of association with MI should be confirmed in a different cohort with better registration for cardiovascular end-points. Furthermore, our plasma metabolomics data warns for potential side effects related to HDL metabolism resulting from LOF in GPR146.
