rs264 — LPL LPL Intron 6 Variant

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.