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

By Fangfang Han, Xiao Liu, Chuanfang Chen, Yinan Liu, Mingkun Du, Yangyang Guan, Yiliang Zhang, Dehe Wang, Musaddeque Ahmed, Xuedan Li, Xiaomin Liu, Yuxian Wu, Yu Zhou, Yong Liu, Bao-Liang Song, Housheng Hansen He, Yan Wang

Posted 10 Jan 2020
bioRxiv DOI: 10.1101/2020.01.09.901041

Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with dyslipidemia. However, about 95% of 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 targeted activation of the rs1997243 site specifically up regulates GPR146 expression in cultured cells. 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. Thus we uncovered a novel G-protein coupled receptor that regulates blood cholesterol level in both human and mouse. Our results also suggest that antagonizing GPR146 function will be an effective strategy to treat hypercholesterolemia.

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