A Key GWAS-identified Genetic Variant Contributes to Hyperlipidemia by Up-regulating miR-320a

Summary It has been unclear whether the elevated levels of the circulating miR-320a in coronary artery disease patients is due to environmental influence or genetic basis. By rAAV-mediated loss- and gain-of-function studies in mouse liver, we revealed that elevated miR-320a is sufficient to aggravate diet-induced hyperlipidemia and hepatic steatosis. Then, we analyzed the data from published GWAS and identified the rs12541335 associated with hyperlipidemia. We demonstrated that the rs13282783 T allele indeed obligated the silencer activity by preventing the repressor ZFP161 and co-repressor HDAC2 from binding to DNA that led to miR-320a up-regulation. We further confirmed this genetic connection on an independent population and through direct genome editing in liver cells. Besides environmental (diet) influence, we established a genetic component in the regulation of miR-320a expression, which suggest a potential therapeutic avenue to treat coronary artery disease by blocking miR-320a in patient liver.