Do common LDLR variants rs688 and rs6511720 affect LDL cholesterol levels?

Common genetic variations in the low-density lipoprotein receptor (LDLR) gene are major determinants of circulating LDL cholesterol (LDL-C) and cardiovascular risk. Extensive research highlights two key variants, rs688 and rs6511720, which modulate lipid profiles through distinct, highly precise molecular pathways.

Clinical evidence and genetic associations

• rs688 (C>T): The minor T allele is associated with elevated plasma total and LDL-C levels. This genetic elevation in circulating cholesterol directly correlates with an increased risk of coronary artery disease and ischemic stroke.
• rs6511720 (G>T): The minor T allele acts as a potent protective factor. Genome-wide association studies (GWAS) by the Global Lipids Genetics Consortium show a highly significant association with reduced LDL-C levels (beta coefficient of approximately -0.22 mmol/L per T allele, $p = 3.85 \times 10^{-262}$), leading to a reduced risk of myocardial infarction and abdominal aortic aneurysm.

Molecular mechanisms and receptor expression

• Post-transcriptional splicing (rs688): The rs688 T-allele disrupts an exonic splicing enhancer (ESE) motif in exon 12, preventing the binding of key splicing factors (SRp40 and SFRS13A). This leads to alternative splicing and exon 12 skipping. The resulting frame-shifted transcripts undergo nonsense-mediated decay (NMD), reducing the expression of functional cell-surface LDL receptors.
• Transcriptional regulation (rs6511720): This intronic variant serves as a cis-regulatory enhancer. The protective T-allele creates a serum response element (SRE) binding site, increasing promoter-reporter activity and upregulating overall LDLR transcription. This increases hepatic receptor density and accelerates the clearance of circulating LDL-C.

Bottom line

• Common LDLR variants rs688 and rs6511720 directly regulate circulating LDL-C levels. The rs688 T-allele reduces functional receptor expression via exon skipping and NMD to increase LDL-C, while the rs6511720 T-allele acts as a transcriptional enhancer to increase receptor expression and lower LDL-C.