LDLR rs688 T raises LDL-C while rs2228671 T lowers it; rs2228671 CC removes the protective effect.

The LDLR gene plays a critical role in cholesterol homeostasis by mediating the clearance of low-density lipoprotein (LDL) particles from the blood. Genetic variations in this gene, specifically at the rs688 and rs2228671 loci, significantly influence an individual's plasma LDL cholesterol (LDL-C) profile and subsequent cardiovascular risk.

Mechanistic basis of rs688 and LDL elevation

The rs688 polymorphism (c.1418C>T) is a synonymous variant located in exon 12 that acts as a potent modifier of splicing efficiency.

• Splicing interference: The T allele disrupts an exonic splicing enhancer (ESE) required for the spliceosome to recognize exon 12. This leads to increased exon skipping and reduced production of mature LDLR mRNA.
• Protein reduction: Resulting mRNA isoforms are often degraded via nonsense-mediated decay (NMD), significantly lowering the density of functional LDL receptors on the cell surface.
• Clinical effect: Functional studies and population data, such as the Framingham Offspring Study, show that the rs688 T allele is consistently associated with higher total and LDL cholesterol levels due to this impaired receptor-mediated clearance.

Protective effects of the rs2228671 T allele

In contrast, the rs2228671 variant is recognized for its protective influence on lipid profiles, particularly in populations of European descent.

• LDL-C reduction: Large-scale meta-analyses (n > 6,600) indicate that each copy of the minor T allele reduces LDL-C by approximately 0.19 mmol/L (p = 1.5×10⁻¹⁰).
• Cardiovascular benefit: This reduction translates into a clinically significant 17% to 18% decrease in the risk of coronary artery disease (OR 0.82–0.83) per T allele.

Genotype interactions and risk

The interplay between these alleles defines the cumulative genetic influence on cholesterol levels.

• Absence of protection: The rs2228671 CC genotype represents the homozygous "wild-type" state that lacks the protective T allele. Because the LDL-lowering effect of rs2228671 is additive and dose-dependent, individuals with the CC genotype do not receive the genetically-driven reduction in LDL-C observed in CT or TT carriers.
• Compounding risk: For an individual carrying the rs688 T allele (which raises LDL via splicing errors), the presence of the rs2228671 CC genotype means there is no compensatory genetic "buffer" to lower LDL-C, potentially leading to higher baseline cholesterol levels.

Bottom line

The claim is strongly supported by scientific evidence. The rs688 T allele raises LDL cholesterol by impairing the splicing of the LDLR gene, while the rs2228671 T allele provides a protective lowering effect. Carrying the rs2228671 CC genotype removes this protection, as the beneficial T allele is absent.