A common polymorphism in the LDL receptor gene has multiple effects on LDL receptor function

Area of Science:

• Genetics
• Molecular Biology
• Cardiovascular Research

Background:

• The synonymous single nucleotide polymorphism (SNP) rs688 in the low-density lipoprotein receptor (LDLR) gene is linked to elevated plasma LDL cholesterol.
• Previous studies suggested rs688 influences LDLR mRNA via alternative splicing and nonsense-mediated decay (NMD).

Purpose of the Study:

• To investigate the functional impact of the synonymous SNP rs688 on full-length LDLR protein and function.
• To determine if rs688 affects LDLR activity through mechanisms beyond alternative splicing.

Main Methods:

• Utilized HepG2 cells expressing LDLR cDNA constructs with either the major or minor allele of rs688.
• Quantified cell surface and lysosomal LDLR protein levels.
• Assessed LDL uptake and response to PCSK9 inhibition.

Main Results:

• The minor allele of rs688 was associated with reduced cell surface LDLR protein and increased lysosomal localization.
• LDL uptake was decreased in cells expressing the minor allele of rs688.
• The minor allele impaired the efficacy of a PCSK9 antibody in enhancing LDL uptake.

Conclusions:

• The synonymous SNP rs688 impacts LDLR protein function, affecting LDLR endosomal recycling and/or PCSK9 binding.
• These findings suggest rs688 influences LDLR activity through co-translational effects, independent of its impact on alternative splicing.
• rs688 represents a functional genetic variant with implications for LDL cholesterol metabolism and cardiovascular risk.