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A common synonymous single nucleotide polymorphism in exon 12 of the low-density lipoprotein receptor ( LDLR ) gene, rs688, has been associated with increased plasma total and LDL cholesterol in several populations. Using immortalized lymphoblastoid cell lines from a healthy study population, we confirmed an earlier report that the minor allele of rs688 is associated with increased exon 12 alternative splicing ( P  &lt; 0.05) and showed that this triggered nonsense-mediated decay (NMD) of the alternatively spliced  LDLR  mRNA. However, since synonymous single nucleotide polymorphisms may influence structure and function of the encoded proteins by co-translational effects, we sought to test whether rs688 was also functional in the full-length mRNA. In HepG2 cells expressing  LDLR  cDNA constructs engineered to contain the major or minor allele of rs688, the latter was associated with a smaller amount of LDLR protein at the cell surface (−21.8 ± 0.6%,  P  = 0.012), a higher amount in the lysosome fraction (+25.7 ± 0.3%,  P  = 0.037) and reduced uptake of fluorescently labeled LDL (−24.3 ± 0.7%,  P  &lt; 0.01). Moreover, in the presence of exogenous proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces cellular LDL uptake by promoting lysosomal degradation of LDLR, the minor allele resulted in reduced capacity of a PCSK9 monoclonal antibody to increase LDL uptake. These findings are consistent with the hypothesis that rs688, which is located in the β-propeller region of  LDLR , has effects on LDLR activity beyond its role in alternative splicing due to impairment of LDLR endosomal recycling and/or PCSK9 binding, processes in which the β-propeller is critically involved.

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