rs2131925 — ANGPTL3 DOCK7/ANGPTL3 Locus Tag SNP

Intronic tag SNP in the DOCK7/ANGPTL3 region; the T allele is associated with higher fasting triglycerides, higher LDL cholesterol, and elevated cardiovascular risk through reduced ANGPTL3-pathway LPL activity

Strong Risk Factor Share

Details

Gene: ANGPTL3
Chromosome: 1
Risk allele: T
Clinical: Risk Factor
Evidence: Strong

Population Frequency

10%

43%

47%

External

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ANGPTL3 — The Triglyceride Clearance Throttle Near Your Lipid Control Center

Your blood lipid levels after a meal depend on how efficiently lipoprotein lipase (LPL) — the enzyme that dismantles triglyceride-rich VLDL and chylomicron particles — can do its job. One of LPL's main regulators is ANGPTL3¹¹ ANGPTL3
Angiopoietin-like protein 3, a liver-secreted protein that inhibits LPL in the circulation, slowing triglyceride clearance. The rs2131925 variant sits in a nearby gene (DOCK7) but tags variation in the ANGPTL3 regulatory region that influences how vigorously this brake is applied.

The Mechanism

ANGPTL3 inhibits LPL by binding to its catalytic site, reducing the rate at which triglycerides are hydrolyzed from circulating lipoprotein particles. When ANGPTL3 activity is higher — as the T allele tags — LPL is more suppressed, triglycerides accumulate in the bloodstream, and the downstream HDL-generating byproducts of lipolysis are reduced. ANGPTL3 also inhibits endothelial lipase²² endothelial lipase
an enzyme that clears HDL particles from circulation; inhibiting it would normally preserve HDL, but this is outweighed by the LPL suppression effect, resulting in a net adverse lipid profile in T allele carriers.

The variant is intronic in DOCK7 and does not alter the ANGPTL3 protein sequence directly. It likely acts as a regulatory tag in high linkage disequilibrium with a functional variant that modulates ANGPTL3 expression or post-translational processing in hepatocytes.

The Evidence

The DOCK7/ANGPTL3 locus was first identified as a genome-wide triglyceride signal in Willer et al. 2008³³ Willer et al. 2008
Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nature Genetics, 2008 across 8,816 individuals. The Global Lipids Genetics Consortium 2010 paper⁴⁴ Global Lipids Genetics Consortium 2010 paper
Teslovich et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature, 2010 in over 100,000 Europeans quantified the effect: each G allele (the protective copy) is associated with 4.94 mg/dL lower fasting triglycerides (95% CI 4.16–5.72, p=9×10⁻⁴³). The association was refined in the 2013 GLGC update⁵⁵ 2013 GLGC update
Willer et al. Discovery and refinement of loci associated with lipid levels. Nature Genetics, 2013 across 188,577 individuals (beta −0.066 log-units, p=3×10⁻⁷⁴).

Beyond lipids, a Finnish case-control study found the T allele was associated with a striking 5-fold increased odds of hypertension in men (OR 5.02, 95% CI 1.40–17.98)⁶⁶ (OR 5.02, 95% CI 1.40–17.98)
Heino & colleagues, Tampere adult population cardiovascular risk study. Lipids Health Dis, 2018, suggesting ANGPTL3-pathway variation may exert direct vascular effects beyond its lipid-lowering influence.

The association replicates across ethnicities: the DOCK7/ANGPTL3 locus was confirmed in African Americans in a transferability study⁷⁷ in a transferability study
Adeyemo et al. Transferability and fine mapping of genome-wide associated loci for lipids across populations. J Clin Lipidol, 2012 of 887 individuals, indicating the signal is not specific to European ancestry.

Practical Actions

For TT carriers — who represent nearly half the European population — the most actionable lever is replacing saturated and refined carbohydrate calories (which promote VLDL synthesis) with omega-3 rich sources that counteract LPL suppression through alternative triglyceride-lowering pathways. High-dose prescription omega-3s (EPA/DHA at 2–4 g/day) achieve clinically meaningful triglyceride reductions through mechanisms that partially bypass the ANGPTL3 brake. Fasting triglyceride monitoring tracks whether compensatory strategies are working.

GT carriers have an intermediate profile and should monitor fasting triglycerides but face less urgent intervention pressure than TT homozygotes.

Interactions

The ANGPTL3/LPL axis overlaps with the ANGPTL4 pathway, which operates tissue- specifically during fasting (particularly in adipose tissue). Variants in ANGPTL4 (e.g., rs2278236) represent a parallel LPL-inhibition mechanism; individuals carrying risk variants at both loci may have compounded triglyceride elevation that exceeds what either variant predicts alone. LPL variants (rs12678919, rs17482753) interact directly at the same enzyme target as ANGPTL3 and may amplify triglyceride effects in compound carriers.

Nutrient Interactions

omega-3 fatty acids altered_metabolism

dietary fat altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant:

GG “Protective Genotype” Beneficial

Double protective G allele — genetically lower triglycerides

The GG genotype is the GRCh38 reference state at this locus. Large GWAS studies consistently show the G allele is the triglyceride-lowering allele — each G copy is associated with approximately 4.94 mg/dL lower triglycerides (Teslovich 2010, Nature). GG individuals therefore start from a genetically favorable lipid baseline at this locus. Dietary fat composition and carbohydrate intake still influence your triglyceride levels, but your genetic floor at this locus is low. No specific intervention is required on the basis of this genotype alone.

GT “One Risk Allele” Intermediate Caution

One T allele — modestly elevated triglyceride tendency

The additive inheritance pattern means each G allele reduces triglycerides by approximately 4.94 mg/dL (Teslovich 2010), so GT carriers fall between GG and TT. Fasting triglycerides typically run 3–5 mg/dL higher in GT than GG carriers on average, which is modest but directionally adverse. The Finnish hypertension study (Heino et al. 2018) found an association between the T allele dose and hypertension risk, suggesting that triglyceride-mediated or direct vascular effects accumulate even in heterozygotes. Dietary fat quality and omega-3 intake remain actionable modulators.

TT “Two Risk Alleles” High Risk Warning

Two T alleles — genetically higher triglycerides at this locus

The TT genotype places you at the high end of the triglyceride distribution attributable to this locus. With two T alleles, you have maximal ANGPTL3-pathway LPL suppression from this variant — both copies contribute to reduced triglyceride-rich particle clearance. This effect is additive: each T allele adds roughly 4.94 mg/dL (Teslovich 2010 estimate) to fasting triglycerides. In high-carbohydrate or high-saturated-fat dietary contexts, the baseline elevation from this variant can compound into clinically significant hypertriglyceridemia. The Finnish hypertension study (Heino et al. 2018, PMID 29989339) found the T allele associated with OR 5.02 for hypertension, suggesting the ANGPTL3 locus may exert direct arterial effects beyond triglyceride levels. Monitoring non-HDL cholesterol alongside triglycerides gives a fuller picture of residual cardiovascular risk at this locus.