Does SORT1 affect hepatic ApoB and VLDL handling, and does the rs646776 T allele lack the LDL-lowering SORT1 signal?

The 1p13.3 genetic locus containing the CELSR2–PSRC1–SORT1 gene cluster represents one of the most significant common genetic determinants of circulating low-density lipoprotein cholesterol (LDL-C). Hepatic Sortilin 1 (SORT1) serves as a critical sorting receptor regulating systemic lipid profiles.

Molecular and hepatic mechanisms

• Intracellular trafficking: SORT1 binds newly assembled apolipoprotein B-100 (ApoB)-containing pre-VLDL particles in the trans-Golgi network.
• Autophagic degradation: Instead of promoting secretion, SORT1 routes these particles toward a pre-secretory proteolytic pathway (PERPP). This pathway relies on an autophagy-dependent endolysosomal route, packaging SORT1–ApoB complexes into amphisomes for lysosomal degradation, acting as a vital quality-control checkpoint.

Genetic influence of the rs646776 variant

• Regulatory eQTL proxy: The rs646776 variant is a robust liver expression quantitative trait locus (eQTL) proxy in strong linkage disequilibrium with the causal 1p13 variant rs12740374, which directly modulates liver SORT1 expression by altering a CEBP transcription factor binding site.
• Allelic differences: The protective minor C allele drives high hepatic SORT1 expression, leading to enhanced intracellular VLDL/ApoB degradation and lower circulating LDL-C.
• The T allele risk: The major ancestral T allele lacks this protective, expression-enhancing signal. Carriers of the T allele exhibit reduced hepatic SORT1 expression, allowing more ApoB-containing particles to escape to the secretory pathway, which increases circulating LDL-C and total cholesterol levels.

Bottom line

• The claim is highly supported: the rs646776 T allele serves as a proxy for reduced hepatic SORT1 expression, which diminishes the autophagy-lysosomal degradation of ApoB and ultimately leads to elevated circulating LDL-C and ApoB-containing particles.