Can HMGCR rs3846662 influence cholesterol synthesis and LDL levels?

Genetic variations within the HMGCR gene represent a primary driver of inter-individual variability in circulating lipids and response to cardiovascular therapies.

Splicing and molecular mechanisms

The intronic single nucleotide polymorphism (SNP) rs3846662 acts as a key cis-splicing regulator. The presence of the regulatory A allele recruits the alternative splicing factor heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) to promote the skipping of exon 13. Rather than altering total HMGCR expression, this genetic shift increases the proportion of the alternative Δexon13 (HMGCR13(−)) transcript. Because exon 13 encodes a critical segment of the HMG-CoA reductase catalytic domain, this truncated isoform is catalytically inactive.

Cholesterol synthesis and LDL clearance

A higher ratio of Δexon13 to full-length HMGCR reduces total functional HMG-CoA reductase activity in hepatocytes, suppressing endogenous cholesterol biosynthesis. To compensate for depleted intracellular cholesterol pools, hepatocytes upregulate surface low-density lipoprotein (LDL) receptors. This enhances the clearance of circulating apolipoprotein B-containing particles, driving down baseline plasma LDL cholesterol levels.

Clinical implications and therapeutic response

• Statin Efficacy: Because the Δexon13 isoform lacks a fully functional drug-binding pocket, carriers of the splicing-associated rs3846662 allele exhibit a blunted therapeutic LDL-lowering response to statins.
• Neurological Risk: Beyond cardiovascular health, this alternative splicing variation is linked to altered Alzheimer's disease risk and progression, likely mediated by shifts in brain cholesterol homeostasis.

Bottom line

• The HMGCR rs3846662 variant alters endogenous cholesterol synthesis and baseline LDL levels by promoting the alternative splicing of exon 13, creating a catalytically inactive enzyme isoform that simultaneously blunts the lipid-lowering efficacy of statin therapy.