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Objective— The noncoding single-nucleotide polymorphism rs12740374 has been hypothesized to be the causal variant responsible for liver-specific modulation ofSORT1 (sortilin 1) expression (ie, expression quantitative trait locus) and, by extension, the association of theSORT1 locus on human chromosome 1p13 with low-density lipoprotein cholesterol levels and coronary heart disease. The goals of this study were to compare 3 different hepatocyte models in demonstrating that the rs12740374 minor allele sequence is responsible for transcriptional activation ofSORT1 expression.Approach and Results— We found that although primary human hepatocytes of varied rs12740374 genotypes strongly replicated theSORT1 expression quantitative trait locus observed previously in whole-liver samples, a population cohort of induced pluripotent stem cell–derived hepatocyte-like cells poorly replicated the expression quantitative trait locus. In primary human hepatocytes from multiple individuals heterozygous at rs12740374, we used CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats–associated 9) to specifically target the rs12740374 minor allele sequence ex vivo, resulting in a reproducible reduction inSORT1 expression. We generated a locus-humanized transgenic mouse with a bacterial artificial chromosome bearing the humanSORT1 locus with the rs12740374 minor allele. In this mouse model, we used CRISPR-Cas9 to target the rs12740374 minor allele sequence in the liver in vivo, resulting in a substantial reduction of hepaticSORT1 expression.Conclusions— The rs12740374 minor allele sequence enhancesSORT1 expression in hepatocytes. CRISPR-Cas9 can be used in primary human hepatocytes ex vivo and locus-humanized mice in vivo to interrogate the function of noncoding regulatory regions. Induced pluripotent stem cell–derived hepatocyte-like cells experience limitations that prevent faithful modelling of some hepatocyte expression quantitative trait loci.

arteriosclerosis, thrombosis, and vascular biology

Interrogation of the Atherosclerosis-Associated <i>SORT1</i> (Sortilin 1) Locus With Primary Human Hepatocytes, Induced Pluripotent Stem Cell-Hepatocytes, and Locus-Humanized Mice

Interrogation of the Atherosclerosis-Associated SORT1 (Sortilin 1) Locus With Primary Human Hepatocytes, Induced Pluripotent Stem Cell-Hepatocytes, and Locus-Humanized Mice