rs5181 — LRP8 Trp466Cys

Rare missense variant in the ApoE receptor 2 (LRP8) ligand-binding domain, disrupting a conserved tryptophan involved in apolipoprotein E-mediated lipid uptake and cholesterol homeostasis in adipocytes and macrophages

See your personal result for LRP8

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

LRP8 Trp466Cys — An ApoE Receptor Variant at the Lipid Uptake Interface

The LRP8 gene11 LRP8 gene
encodes ApoER2, apolipoprotein E receptor 2, a member of the LDL receptor superfamily that binds apolipoprotein E-enriched lipoproteins and mediates their endocytosis into cells. While LRP8 is best known for its role in neuronal Reelin signaling, it is also prominently expressed in adipocytes and macrophages, where it participates in apoE-directed lipid trafficking — making variants in this gene of potential relevance to fat storage and cardiovascular risk.

The Trp466Cys variant (rs5181) replaces a conserved tryptophan residue in the ligand-binding domain of LRP8 with a cysteine. Tryptophan residues in LDL receptor family ligand-binding repeats typically participate in the hydrophobic core of beta-hairpin structures22 hydrophobic core of beta-hairpin structures
The beta-hairpin fold positions the acidic residues that coordinate calcium and create the ligand-docking surface, and their substitution with cysteine introduces a free thiol group that can disrupt disulfide bonding patterns, potentially altering receptor conformation and ligand-binding affinity.

Note: Population frequency data for this variant are not available in current major databases (gnomAD, 1000 Genomes), indicating it is rare or population-restricted. The clinical interpretation below is based on the known biology of the LRP8 ligand-binding domain and the functional consequences documented for other LRP8 missense variants. Direct evidence for the Trp466Cys change specifically is limited to its presence in sequencing datasets — no functional studies or large association studies have examined this specific variant.

The Mechanism

LRP8 (ApoER2) contains an N-terminal ligand-binding domain33 N-terminal ligand-binding domain
Composed of cysteine-rich LDL receptor type A repeats that coordinate calcium ions to create the binding surface for apolipoprotein E-containing lipoproteins including beta-VLDL and HDL comprising multiple LDLa repeats. Tryptophan 466 (in the canonical 870-amino-acid isoform) sits within this domain. In adipocytes — where LRP8 is overexpressed approximately 14-fold relative to whole-body average expression — the receptor is thought to mediate apoE-dependent uptake of triglyceride-rich lipoproteins alongside the more extensively studied LRP1 and VLDL receptor.

In macrophages, ApoER2/LRP8 deficiency has been shown to enhance lipid accumulation and susceptibility to oxidized LDL-induced cell death44 ApoER2/LRP8 deficiency has been shown to enhance lipid accumulation and susceptibility to oxidized LDL-induced cell death
Zhou L et al. Apolipoprotein E receptor-2 deficiency enhances macrophage susceptibility to lipid accumulation and cell death to augment atherosclerotic plaque progression and necrosis. Biochimica et Biophysica Acta, 2014. ApoER2 limits PPARγ expression in macrophages and promotes cholesterol efflux via ABCA1, favoring an anti-inflammatory, antiatherogenic macrophage phenotype. A missense variant that disrupts ligand-binding domain integrity could reduce ApoER2-mediated cholesterol efflux, increasing foam cell formation risk.

The Evidence

Direct evidence for rs5181 (Trp466Cys) is limited to its presence in the dbSNP database (build 157) and the Illumina genotyping platform — no functional studies or population association studies have examined this variant specifically.

The broader significance of LRP8 missense variants in fat and lipid metabolism is supported by work on the R952Q variant (rs5174)55 R952Q variant (rs5174)
Shen GQ et al. An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction. Am J Hum Genet, 2007, which encodes a different missense change in LRP8 and has been associated with premature coronary artery disease and elevated plasma triglycerides in independent cohorts. The R952Q variant acts by increasing p38 MAPK activation in response to oxidized LDL, amplifying macrophage inflammatory signaling.

LRP8 has also been associated with triglyceride levels66 LRP8 has also been associated with triglyceride levels
Horne BD et al. Genetic variant R952Q in LRP8 is associated with increased plasma triglyceride levels in patients with early-onset CAD and MI. Lipids in Health and Disease, 2012, further implicating the receptor in lipid homeostasis beyond simple LDL clearance.

ApoER2 deficiency in mice with LDL receptor knockout77 ApoER2 deficiency in mice with LDL receptor knockout
Zhou et al. 2014 resulted in accelerated atherosclerosis with more complex lesions, more foam cell necrosis, and defective macrophage Akt signaling — demonstrating that loss of ApoER2 function in the lipid-laden vascular environment has substantive metabolic and structural consequences.

Practical Implications

Given the rarity of this variant and the absence of direct clinical studies, specific dietary or supplement recommendations tied exclusively to the Trp466Cys change would exceed the available evidence. However, if this missense variant reduces LRP8 function in a manner analogous to deficiency models, the most evidence-consistent implication is a potential reduction in ApoER2-mediated apoE-lipid uptake and macrophage cholesterol efflux — biological events that link to elevated cardiovascular and metabolic risk.

Carriers of rare LRP8 missense variants may benefit from monitoring of cardiovascular risk biomarkers, particularly plasma triglycerides and LDL-C, and from dietary strategies that reduce the load on the ApoE-receptor system (limiting dietary saturated fat reduces apoB-containing lipoprotein production that must be cleared via this pathway).

Interactions

LRP8 interacts with the ApoE pathway, making APOE genotype (specifically ε2/ε3/ε4) a likely modifier of LRP8 variant effects. A study examining the LRP8 R952Q variant found additive effects with APOE ε4 genotype on apoE plasma levels and MI risk, suggesting that carrying both a LRP8 missense variant and the APOE ε4 allele could compound the impairment of apoE-directed lipid clearance. Related SNPs in LRP8 include rs5174 (R952Q, the best-studied missense variant), rs2297660 (associated with birth weight and schizophrenia susceptibility), and rs5177 (3' UTR variant associated with cardiovascular outcomes).

Nutrient Interactions

apolipoprotein E-bound lipids altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal ApoER2 Function Normal

Standard ApoE receptor 2 function with normal apoE-mediated lipid uptake

You carry two copies of the common C allele, preserving the tryptophan residue at position 466 of the LRP8 protein. This is the predominant genotype in all studied populations. Your ApoER2 receptor is expected to maintain normal ligand-binding domain conformation and standard apolipoprotein E-mediated lipid uptake efficiency in adipocytes and macrophages.

CG Reduced ApoER2 Binding Intermediate

One copy of the Trp466Cys variant — potential partial reduction in ApoE receptor function

In cell and animal models, reduced ApoER2/LRP8 function in macrophages impairs cholesterol efflux and increases susceptibility to oxidized LDL-induced lipid accumulation and foam cell formation, a key early event in atherosclerosis. In adipocytes, reduced ApoER2 function could alter postprandial apoE-enriched lipoprotein clearance. The functional consequences of the Trp→Cys substitution at position 466 have not been studied in isolation; however, the LDL receptor family precedent indicates that disulfide pattern disruptions in ligand-binding repeats reduce receptor folding stability and ligand affinity.

GG Disrupted ApoER2 Binding Domain Decreased

Homozygous Trp466Cys — likely substantial reduction in LRP8 ligand-binding domain function

Homozygous loss of ApoER2 function in mouse models results in significantly accelerated atherosclerosis, increased macrophage foam cell formation, and defective Akt/PPARγ signaling in macrophages exposed to oxidized LDL. If the Trp466Cys substitution substantially reduces receptor folding or ligand binding, homozygous carriers may have a cardiovascular risk profile similar to partial ApoER2 deficiency. The strongest known functional analog — the R952Q LRP8 missense variant — shows additive effects with APOE ε4 on apoE plasma levels and MI risk, suggesting that severe LRP8 domain disruption compound with other apoE pathway variants to increase cardiovascular burden.

The absence of population frequency data means the absolute number of GG individuals is unknown; this genotype may be extremely rare or absent in current large cohort databases.