Hypercholesterolemia risk associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol level in human and mouse

Abstract

14 15 2 Genome-wide association studies (GWAS) have identified hundreds of genetic variants 16 associated with dyslipidemia. However, about 95% of of these variants are located in genome 17 noncoding regions and cluster in different loci. The disease-causing variant for each locus and 18 underline mechanism remain largely unknown. We systematically analyzed these noncoding 19 variants and found that rs1997243 is the disease-causing variant in locus 7p22, which is 20 strongly associated with hypercholesterolemia. The rs1997243 risk allele is associated with 21 increased expression of GPR146 in human and targeted activation of the rs1997243 site 22 specifically up regulates GPR146 expression in cultured cells. GPR146 is an orphan G-protein 23 coupled receptor that is located on plasma membrane and responses to stimulation of heat-24 inactivated serum. Disrupting gpr146 specifically in the liver decreases the blood cholesterol 25 level and prevents high-fat or high-fat high-cholesterol diets induced hypercholesterolemia in 26 mice. Thus we uncovered a novel G-protein coupled receptor that regulates blood cholesterol 27 level in both human and mouse. Our results also suggest that antagonizing GPR146 function 28 will be an effective strategy to treat hypercholesterolemia. 29Genome-wide association study (GWAS) is a powerful tool to ascertain the contribution of 30 common genetic variants in population-wide diseases variability. Hundreds of GWAS studies have 31 been applied to a variety of diseases or traits including dyslipidemia, diabetes, and hypertension et 32 al 1 . More than 93% of these disease-and trait-associated variants are located in the non-coding 33 regions, makes it difficult to evaluate their function 2 . Previous studies showed that these disease-34 and trait-associated variants are concentrated in regulatory DNA, with about 80% of all noncoding 35 GWAS single nucleotide polymorphisms (SNPs) or linkage disequilibrium (LD) SNPs are located 36 within DNase I hypersensitive sites (DHS) 2 , which suggest that most of these noncoding SNPs 37 3 function through transcriptional regulation. 38Hypercholesterolemia is the leading risk factor for cardiovascular diseases. Current evidence 39 suggests that the heritability for blood cholesterol level is high, with 40-50% for low-density 40 lipoprotein cholesterol (LDL-C) and 40-60% for high-density lipoprotein cholesterol (HDL-C) 3,4 . 41 GWAS has been performed extensively on blood lipids traits and more than 300 risk loci were found 42 in different populations 5 . These loci cover almost all the well-known genes that are important in 43 lipid metabolism, such as LDLR 6 , ARH 7 , ABCA1 8 , ABCG5/G8 9 , PCSK9 10 , NPC1L1 11,12 , LIMA1 13 , 44 et al. Although GWAS is a powerful approach, we find that about 2/3 of these risk loci are located 45 in noncoding regions and are not close to any gene known plays a role in lipid metabolism. The 46 disease-causing variants in these loci and their underlying molecular mechanism remain largely 47