rs13702 — LPL

LPL rs13702 — The microRNA-410 Switch

Lipoprotein lipase (LPL) is the principal enzyme that clears triglyceride-rich lipoproteins¹¹ triglyceride-rich lipoproteins
Very low-density lipoproteins (VLDL) and chylomicrons — the particles that carry fat from the liver and intestine through the bloodstream from circulation. Most research into LPL genetics has focused on coding variants that change the protein itself. rs13702 works differently: it sits in the 3' untranslated region of the LPL gene, a stretch of mRNA that doesn't code for protein but acts as a regulatory landing pad for microRNAs. The variant's mechanism is one of the clearest examples of non-coding genetic regulation affecting a clinically important phenotype.

The Mechanism

The LPL 3' UTR at rs13702 contains a recognition element for microRNA-410 (miR-410). MicroRNAs are short non-coding RNA molecules that bind to target sequences in mRNA and suppress gene expression — they act as a molecular volume knob, turning down the amount of protein produced. When miR-410 binds its recognition element in the LPL 3' UTR, it reduces LPL mRNA translation, lowering the amount of lipoprotein lipase enzyme made.

The rs13702 T allele (the common reference sequence) preserves this binding site intact. miR-410 binds normally, and LPL expression is held under its natural degree of suppression. The C allele, which disrupts the miR-410 seed-sequence match²² seed-sequence match
The "seed" region of a microRNA is its 6–8 nucleotide core that determines target recognition. A single nucleotide change that disrupts complementarity at the seed is enough to abolish binding entirely, prevents miR-410 from binding. Without this brake, luciferase reporter assays³³ luciferase reporter assays
Laboratory experiments where the LPL 3'UTR is fused to a reporter gene — if the mRNA is suppressed, less light is produced. These assays demonstrated the T allele was suppressed 40% by miR-410 mimics, while the C allele was not suppressed at all showed that the T-allele LPL mRNA is reduced by approximately 40% when miR-410 is present, whereas the C-allele reporter is completely unaffected. The result is that C-allele carriers produce more LPL enzyme, clear triglycerides more efficiently, and generate more HDL cholesterol as a byproduct of lipolysis.

The Evidence

Richardson et al.⁴⁴ Richardson et al.
Richardson K et al. Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. Am J Hum Genet, 2013 performed the definitive characterisation of this variant in a meta-analysis across ten population cohorts. Each copy of the C allele was associated with −0.060 mmol/L lower plasma triglycerides (p = 3.18 × 10⁻⁴²) and +0.041 mmol/L higher HDL cholesterol (p = 1.35 × 10⁻³²) — effects equivalent to roughly a 3–5% reduction in fasting triglycerides per allele copy. The study also showed that the lipid-lowering effect of the C allele was amplified in the presence of higher dietary polyunsaturated fat intake (p = 0.00153 for interaction), adding a dietary dimension to the gain-of-function biology.

The CARDIA study Tang et al.⁵⁵ Tang et al.
Tang W et al. Associations of LPL gene polymorphisms with longitudinal plasma lipid trends in young adults. Circ Cardiovasc Genet, 2010 followed 4,161 individuals for 20 years, finding that the C allele not only conferred lower triglycerides and higher HDL at baseline but also slowed the age-related trajectory of worsening lipids — the protective benefit accumulates over a lifetime.

The PREDIMED randomised controlled trial Corella et al.⁶⁶ Corella et al.
Corella D et al. MicroRNA-410 regulated lipoprotein lipase variant rs13702 is associated with stroke incidence and modulated by diet in the randomized controlled PREDIMED trial. Am J Clin Nutr, 2014 examined stroke incidence and found that T-allele homozygotes had elevated stroke risk compared to C-allele carriers. Crucially, assignment to a Mediterranean diet pattern eliminated this excess risk in T-allele carriers — a direct demonstration that dietary fat quality modifies the consequences of reduced LPL activity through this microRNA mechanism.

Dietary modulation was confirmed by Hammad et al.⁷⁷ Hammad et al.
Hammad et al. Common Variants in Lipid Metabolism-Related Genes Associate with Fat Mass Changes in Response to Dietary MUFA in Adults with Abdominal Obesity. J Nutr, 2019, who found that CC homozygotes on high-MUFA diets achieved significantly greater visceral fat reduction (−216 g vs. +17 g in TT carriers, p = 0.017), suggesting the protective effect of the C allele is potentiated by replacing saturated fat with monounsaturated fat.

The C allele frequency varies considerably by ancestry: approximately 29% in Europeans, 51% in Africans, 20% in East Asians, 24% in South Asians, and 30% in Latinos. Most individuals carry at least one C allele, but around 42% of the global population carries TT — the genotype with standard, unmodified LPL expression.

Practical Implications

This is a protective variant. C-allele carriers benefit from the gain-of-function effect automatically — they clear triglycerides more efficiently and maintain higher HDL. The evidence for TT homozygotes points to a meaningful advantage to optimising LPL activity through diet: replacing saturated fat with monounsaturated and polyunsaturated fats (Mediterranean-style dietary fat quality, not simply fat quantity) appears to partially compensate for the absence of the miR-410 disruption. Omega-3 polyunsaturated fatty acids (EPA and DHA) reduce VLDL secretion and upregulate LPL expression through PPAR-α — a mechanistically relevant intervention for T-allele carriers who lack the genetic braking relief of the C allele.

Interactions

rs13702 and rs264 (LPL intron 6) are both LPL regulatory variants but operate through distinct mechanisms: rs264 modulates intronic regulatory elements or splicing enhancers, while rs13702 specifically disrupts a post-transcriptional miRNA regulatory step. They may reside on independent haplotypes. The gain-of-function coding truncation rs328 (S447X) raises LPL activity through a different route (altered heparin-binding and clearance kinetics) and may combine additively with the rs13702 C allele. APOA5 variants (including rs662799 upstream of the gene) reduce LPL stimulation; TT carriers at rs13702 who also carry APOA5 risk alleles face a compounded deficit in triglyceride clearance capacity.