rs264 — LPL LPL Intron 6 Variant

Intronic LPL variant associated with altered triglyceride clearance and HDL levels; the minor A allele is linked to lower HDL cholesterol and elevated coronary artery disease risk

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LPL Intron 6 — The Triglyceride Clearance Regulator

Lipoprotein lipase (LPL) is the central enzyme that clears triglyceride-rich particles11 triglyceride-rich particles
Very low-density lipoproteins (VLDL) and chylomicrons — the main carriers of dietary and liver-made fats in the bloodstream from circulation. LPL activity sets the pace for how quickly you clear fat from your blood after eating. The rs264 variant, located in intron 6 of the LPL gene (NM_000237.3:c.776-172G>A), is an intronic polymorphism with genome-wide-significant associations with circulating triglyceride and HDL cholesterol levels.

The Mechanism

As an intronic variant 172 nucleotides upstream of exon boundaries, rs264 does not directly alter the LPL protein sequence. Intronic LPL variants like rs264, the classical HindIII polymorphism (rs320, intron 8), and the PvuII polymorphism (rs285, intron 6) are thought to influence LPL expression or mRNA processing through effects on regulatory elements or splicing enhancers22 regulatory elements or splicing enhancers
Intronic sequences can contain binding sites for transcription factors, splicing regulatory proteins, and microRNAs. Changes in these elements alter how much protein is made, or whether alternative splice forms are produced. The nearby functional variant rs13702 (3′ UTR of LPL) is a well-characterised gain-of-function allele that disrupts a microRNA-410 binding site; rs264 lies in a different regulatory region and may affect expression via a distinct mechanism. Carriers of the minor A allele tend to show phenotypic patterns consistent with modestly reduced LPL activity — higher triglycerides and lower HDL cholesterol — without the severity seen in coding loss-of-function mutations.

The Evidence

The LPL locus is one of the strongest genetic determinants of circulating lipids. Teslovich et al.33 Teslovich et al.
Teslovich NM et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature, 2010 identified LPL as a genome-wide-significant locus for both triglycerides and HDL-C in a meta-analysis of over 100,000 individuals. Within the LPL region, Peloso et al.44 Peloso et al.
Peloso GM et al. Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 adults. JAMA, 2014 confirmed rs264 as part of the LPL haplotype block associated with lower triglycerides (p=5×10⁻⁴⁶), higher HDL-C (p=7×10⁻⁴⁸), and inverse CAD risk (p=3×10⁻⁹), with the common G allele carrying the beneficial lipid-lowering direction.

Population studies have provided direct evidence for the minor A allele. Osman et al.55 Osman et al.
Osman W et al. Genetics of type 2 diabetes and coronary artery disease and their associations with twelve cardiometabolic traits in the UAE population. PLOS ONE, 2020 found the strongest CAD association in their UAE cohort at rs264 (OR=1.96 for allele A, p=0.009) and noted that the AA genotype was enriched among patients with type 2 diabetes. A 2024 case-control study Laszlo et al.66 Laszlo et al.
Laszlo L et al. LPL rs264, PROCR rs867186 and PDGF rs974819 gene polymorphisms in patients with unstable angina. J Pers Med, 2024 confirmed lower serum HDL levels in AA carriers compared to GA heterozygotes, though rs264 alone did not independently predict unstable angina risk in a European cohort — consistent with it being a moderate-effect modifier rather than a major causal variant.

The A allele minor frequency varies from ~13% in African populations to ~20% in East Asian populations, meaning that about 2% of people globally carry two copies (AA genotype), with the greatest burden in East Asian ancestry groups.

Practical Implications

The actionable context of rs264 centres on LPL activity optimisation. Because the A allele is associated with modestly reduced LPL-mediated clearance of triglyceride-rich particles, dietary strategies that reduce the triglyceride load entering circulation and pharmacological approaches that boost LPL activity are particularly relevant. Omega-3 fatty acids (EPA/DHA) reduce hepatic VLDL secretion and, via PPAR-α activation, upregulate LPL gene expression — making them a mechanistically targeted intervention for A-allele carriers. Limiting dietary refined carbohydrates and fructose reduces the hepatic triglyceride production that LPL must clear. Fasting lipid panels are the key monitoring tool: triglycerides and HDL-C are the direct readout of LPL functional capacity.

Interactions

The LPL gene harbours multiple functionally relevant variants that operate independently. The gain-of-function S447X variant (rs328, exon 9) generates a truncated LPL protein with paradoxically higher lipolytic activity; rs328 and rs264 may be on different haplotype backgrounds. The HindIII RFLP (rs320, intron 8) is another intronic variant with lipid associations; rs320 and rs264 are in partial LD and their combined effect is likely additive. APOA5 S19W (rs3135506) reduces LPL stimulation by apoAV and raises triglycerides independently; APOA5 + LPL variant combinations have documented additive effects on hypertriglyceridemia risk (ICARIA study, PMID 20429872). ANGPTL4 (rs116843064) inhibits LPL; a partial loss-of-function ANGPTL4 allele has additive protective effects when combined with LPL gain-of-function variants. For individuals with rs264 AA combined with other LPL/APOA5 triglyceride-raising variants, fasting triglycerides should be monitored carefully given the cumulative risk.

Nutrient Interactions

omega-3 fatty acids increased_need
refined carbohydrates altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal LPL Activity Normal

Standard LPL triglyceride clearance — no elevated lipid risk from this variant

You carry two copies of the common G allele at rs264, the reference configuration for this intronic LPL variant. Your LPL gene expression from this locus is expected to be unaffected, supporting normal triglyceride clearance and HDL production. About 73% of people of all ancestries share this genotype.

AG Heterozygous Carrier Intermediate

One copy of the A allele — modest trend toward lower HDL and altered triglyceride clearance

The A allele at rs264 is in the intronic regulatory region of LPL and is associated with reduced LPL-related lipid clearance capacity. In heterozygous carriers, one functional copy of the G-reference allele partially compensates, resulting in a mild rather than marked lipid phenotype. The key actionable parameters are fasting triglycerides and HDL-C. Carriers with additional triglyceride-raising variants (APOA5 S19W, APOC3 -455T>C, ANGPTL4 common) may show a more pronounced combined effect. The UAE population study (PMID 32360841) observed the strongest individual-variant CAD signal at this locus, underscoring the value of lipid monitoring even in heterozygous carriers.

AA Homozygous A Allele High Risk

Two copies of the A allele — lower HDL, elevated CAD and type 2 diabetes risk

The AA genotype at rs264 represents the most pronounced form of LPL intronic-variant-mediated lipid imbalance. Both copies of the A allele are associated with reduced LPL expression from this regulatory region, leading to compromised triglyceride-rich lipoprotein clearance. The downstream consequences are lower HDL cholesterol (HDL particles are generated as a byproduct of LPL-mediated VLDL hydrolysis, so less LPL activity = fewer HDL precursors) and higher residual triglyceride-rich remnant particles that promote atherosclerosis.

The UAE Emirati population study (Osman et al., PMID 32360841, n=914) found that rs264 produced the strongest single-variant CAD signal in their genome, with the A allele carrying OR=1.96 for coronary artery disease. AA carriers also showed enrichment for type 2 diabetes, consistent with the known link between hypertriglyceridemia, reduced HDL, and insulin resistance.

Clinically, management targets the underlying LPL-pathway deficit: maximise dietary and supplemental approaches that reduce the triglyceride clearance demand (lower carbohydrate, lower saturated fat), while interventions that support LPL activity or reduce VLDL input (omega-3s, fibrates if indicated) address the root pathway.