Can LDLR rs688 CT reduce LDL receptor splicing efficiency and LDL clearance?

LDLR rs688 is a synonymous exon-12 C>T variant with reproducible effects on LDLR RNA processing. For a 53-year-old woman with CT genotype, the T allele provides a biologically credible—though not clinically quantified—route to modestly reduced LDL receptor–mediated LDL handling.

Splicing and molecular mechanism

• The T allele modestly favors LDLR exon 12 skipping. In postmortem liver, exon-12 inclusion differed by about 8.6% between female CC and TT homozygotes (P=0.024); HepG2 minigenes showed roughly 12% lower inclusion with the T allele.
• Allele-substitution minigene work supports a direct cis-regulatory effect, plausibly through weakening an exon-splicing enhancer predicted to affect SRp40 binding.
• Exon-12-skipped LDLR RNA is frameshifted, contains a premature stop codon, and is targeted by nonsense-mediated decay. Thus, increased skipping could reduce the amount of functional LDLR transcript.

LDL uptake and hepatic-clearance implications

• In a HepG2 cDNA model, the T-allele construct had 21.8% lower cell-surface LDLR abundance and 24.3% lower fluorescent-LDL uptake, with greater lysosomal receptor localization. These results support reduced receptor-mediated cellular LDL uptake.
• This creates a coherent mechanism by which CT status could modestly impair hepatic LDL-particle clearance. However, the cDNA system bypasses the splicing step and does not measure whole-body or liver-specific LDL clearance.

Clinical interpretation

• Human lipid associations are variable. In Framingham, T-allele carriers had higher LDL-C mainly among women, with similar effects reported for CT and TT; a Taiwanese cohort also reported higher hyperlipidemia odds for CT women.
• No study has directly measured hepatic LDL uptake or LDL-apoB fractional catabolic rate in CT carriers.

Bottom line

• rs688 CT plausibly contributes to less efficient LDLR-mediated LDL clearance, particularly in women, but it is not a demonstrated human clearance phenotype and should not be interpreted as a stand-alone determinant of LDL-C or cardiovascular risk.