LAUSR

It is challenging to study regulatory genetic variants as gene expression is affected by both genetic polymorphisms and non‐genetic regulators. The mRNA allele‐specific expression (ASE) assay has been increasingly used for the study of cis‐acting regulatory variants because cis‐acting variants affect gene expression in an allele‐specific manner. However, poor correlations between mRNA and protein expressions were observed for many genes, highlighting the importance of studying gene expression regulation at the protein level. In the present study, we conducted a proof‐of‐concept study to utilize a recently developed allele‐specific protein expression (ASPE) assay to identify the cis‐acting regulatory variants of CES1 using a large set of human liver samples. The CES1 gene encodes for carboxylesterase 1 (CES1), the most abundant hepatic hydrolase in humans. Two cis‐acting regulatory variants were found to be significantly associated with CES1 ASPE, CES1 protein expression, and its catalytic activity on enalapril hydrolysis in human livers. Compared to conventional gene expression‐based approaches, ASPE demonstrated an improved statistical power to detect regulatory variants with small effect sizes since allelic protein expression ratios are less prone to the influence of non‐genetic regulators (e.g., diseases and inducers). This study suggests that the ASPE approach is a powerful tool for identifying cis‐regulatory variants.