Human Genetics and Dyslipidemia: From Non-synonymous Variants to Non-coding Variants

Abstract

Dyslipidemia has strong heritability, with over 50% of dyslipidemia is caused by genetics in general population. Previously studies identify many non-synonymous variants in genes of LDLR, PCSK9, ANGPTL3, ABCG5/8, ARH et.al, which lay the fundation for durg development. However, these known non-synonymous variants can only explain about 10-20% of genetic risks. Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with dyslipidemia in large population. However, about 95% of these variants are located in genome noncoding regions and cluster in different loci. The disease-causing variant for each locus and underline mechanism remain largely unknown. We systematically analyzed these noncoding variants and found that rs1997243 is the disease-causing variant in locus 7p22, which is strongly associated with hypercholesterolemia. The rs1997243 risk allele is associated with increased expression of GPR146 in human and specifically up regulates GPR146 expression in cultured hepatocytes. GPR146 is an orphan G-protein coupled receptor that is located on plasma membrane and responses to stimulation of heat-inactivated serum. Disrupting gpr146 specifically in the liver decreases the blood cholesterol level and prevents high-fat or high-fat high-cholesterol diets induced hypercholesterolemia in mice. Mechanistic study suggests that GPR146 regulates blood cholesterol level mainly through regulating the catabolism of cholesterol rich lipoprotein particles. Thus we uncovered a novel G-protein coupled receptor that regulates blood cholesterol levels in both humans and mice. Our results also suggest that antagonizing GPR146 function will be an effective strategy to treat hypercholesterolemia. National Key Research and Development Program of China (2018YFA0800700), the National Natural Science Foundation of China (92057207, 91754101, 32021003, 31771304) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.