Does the rs12740374 variant in SORT1 lower LDL cholesterol?

The 1p13 chromosomal locus is recognized as one of the most robust genetic determinants of plasma lipid levels and cardiovascular risk identified through genome-wide association studies (GWAS). Central to this association is the SORT1 gene, which encodes the protein sortilin, a multi-ligand sorting receptor that plays a critical role in hepatic lipoprotein metabolism.

Clinical and genomic evidence

The rs12740374 variant is a primary functional single nucleotide polymorphism (SNP) at the 1p13 locus. Meta-analyses of GWAS involving over 100,000 participants consistently link this variant to significant variations in low-density lipoprotein cholesterol (LDL-C). Specifically, the minor allele (G) of rs12740374 creates a novel binding site for the transcription factor C/EBPα in human hepatocytes. This gain-of-function mutation leads to a 12-fold increase in SORT1 mRNA expression in the liver. Clinical data demonstrate that individuals carrying this minor allele exhibit lower circulating levels of LDL-C, which translates to a reduced risk of myocardial infarction (odds ratio ~0.8 per allele).

Mechanistic explanations

Sortilin regulates plasma cholesterol through a dual mechanism affecting both the production and clearance of apolipoprotein B (apoB)-containing lipoproteins:

• Inhibition of secretion: Sortilin binds to apoB-100 within the endoplasmic reticulum and Golgi apparatus. High levels of sortilin divert apoB-100 from the secretory pathway toward presecretory lysosomal degradation via autophagy. This reduces the hepatic secretion of very-low-density lipoproteins (VLDL), the precursors to LDL.
• Enhanced uptake: Sortilin functions as an alternative receptor for LDL particles at the plasma membrane. It facilitates the endocytosis and subsequent lysosomal trafficking of LDL, thereby increasing the rate of catabolism and clearance from the circulation. Sortilin also interacts with other key regulators, such as PCSK9, further modulating the availability of the LDL receptor (LDLR).

Bottom line

The rs12740374 variant is a well-validated causal modulator of human LDL cholesterol levels. It functions by upregulating hepatic SORT1 expression, which simultaneously reduces the secretion of VLDL and enhances the clearance of circulating LDL particles.