A functional SNP rs12718466 in APOA1 promoter modulates gene expression via interaction with SOX7.

Plasma concentration of high-density lipoprotein cholesterol (HDL-C) is among the most important risk factors for coronary artery disease and apolipoprotein A1 (APOA1) is an essential apolipoprotein that constitutes HDL. However, few comprehensive searches have been conducted to identify noncoding functional SNPs around the APOA1 gene. In this study, we report the identification of a functional SNP, rs12718466, which influences hepatocyte-specific APOA1 gene expression. Furthermore, we identified SRY-box transcription factor 7 (SOX7) as the transcription factor interacting with the rs12718466 SNP, using a novel screening method Transcription Factor Expression Library scan, which employs a comprehensive library of mouse transcription factors. SOX7 binding is allele-dependent, with stronger binding to the normal allele leading to increased APOA1 transcription. In vitro experiments in hepatocytes and in vivo experiments in mice confirmed that overexpressing SOX7 increased APOA1 expression, while knocking it down decreased both APOA1 gene expression and plasma HDL-C levels. Our research demonstrates that rs12718466 is a functional SNP that modulates APOA1 gene expression through its interaction with SOX7, thereby affecting plasma HDL-C concentrations.