rs4775065 — LIPC

Intronic LIPC variant associated with susceptibility to low HDL-C and coronary heart disease through hepatic lipase activity modulation; A allele (minor, ~29% globally) confers elevated CHD risk

See your personal result for LIPC

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.

LIPC rs4775065 — A Hepatic Lipase Variant That Remodels Your Cardiovascular Risk Landscape

Your liver sits at the end of the lipoprotein remodeling pipeline. After peripheral tissues have stripped triglycerides from VLDL using lipoprotein lipase, the leftover remnant particles — along with large, buoyant HDL2 — return to the liver surface, where hepatic lipase (encoded by LIPC) performs the final cleanup: hydrolyzing residual triglycerides and phospholipids, converting HDL2 to smaller, denser HDL3 particles, and clearing IDL particles back into the LDL pool. This remodeling step shapes the HDL particle size distribution and clears atherogenic remnant lipoproteins from the bloodstream.

The rs4775065 variant sits in an intron of LIPC at chromosome 15q22 (GRCh38 position 58,509,744). The minor A allele (approximately 29% globally, with the G allele as the common protective form) has been linked to elevated susceptibility to the combined low HDL-C and coronary heart disease (CHD) phenotype. Notably, this is an intronic variant — it does not change the LIPC protein directly, but likely influences hepatic lipase expression or splicing through regulatory effects on the gene.

The Mechanism

Hepatic lipase11 Hepatic lipase
HL; encoded by LIPC — a phospholipase and triglyceride lipase anchored to liver sinusoidal endothelium that clears IDL, VLDL remnants, and remodels HDL2 into HDL3 is central to the final step of lipoprotein remodeling. Variants that reduce HL activity preserve large HDL2 particles (raising nominal HDL-C) but also slow clearance of atherogenic remnant particles. Conversely, variants that raise HL activity produce smaller HDL3 and can lower the measured HDL-C.

The rs4775065 intronic position suggests it may tag an expression-regulatory signal or be in LD with a functional regulatory element that has not yet been fully resolved.

The Peloso 2010 study found an intriguing dissociation: the A allele showed a very strong association with the combined low HDL-C + CHD case phenotype (OR 2.36 for heterozygotes, P=3.82×10⁻¹⁰ by 2df test), yet was not significantly associated with HDL-C levels alone when comparing controls stratified by their HDL. This suggests rs4775065 may influence CHD susceptibility through a pathway beyond simple HDL-C quantity — possibly affecting HDL particle function, remnant clearance, or triglyceride metabolism in a way not captured by the standard HDL-C number.

The Evidence

The primary evidence comes from a candidate-gene association study by Peloso et al.22 candidate-gene association study by Peloso et al. examining 60 metabolic-pathway genes in 699 men with low HDL-C and established CHD (VA-HIT trial) versus 705 CHD-free controls from the Framingham Offspring Study. Among all 60 candidate loci, rs4775065 in LIPC showed the single strongest association with case status: the A allele minor allele frequency was 0.33 in cases versus 0.23 in controls. Heterozygous AG individuals had an OR of 2.36 (95% CI 1.83–3.05), and the overall 2-degree-of-freedom genotypic test reached P=3.82×10⁻¹⁰. After lipid adjustment, the association remained significant (P=1.15×10⁻⁶), confirming that the variant's relationship to CHD risk is not fully mediated through measured lipid levels.

The Feitosa et al. study33 Feitosa et al. study of 591 NHLBI Family Heart Study families demonstrated that LIPC intron 1 variants modify HDL-C in a sex-specific fashion — with some variants showing female-predominant effects mediated through hormonal influences on hepatic lipase expression.

The evidence level is moderate: the primary association study was not a genome-wide scan (it was a candidate-gene study with a pre-specified hypothesis about these 60 loci), but the statistical signal was exceptionally strong for a candidate-gene analysis.

Practical Actions

For GG homozygotes (approximately 50% of people globally), the common LIPC allele at this locus is associated with standard hepatic lipase function. The CHD risk signal at this locus is not elevated.

For AG heterozygotes (approximately 41% globally), one A allele at rs4775065 is associated with approximately 2.4-fold higher odds of the combined low HDL-C and CHD phenotype compared to GG carriers. Monitoring triglycerides and HDL-C together — rather than treating HDL-C in isolation — is more informative, as the LIPC pathway affects both fractions. Omega-3 fatty acids (EPA/DHA) directly support hepatic lipase activity and improve HDL particle remodeling.

For AA homozygotes (approximately 8.5% globally), two A alleles carry the highest risk at this locus. A full lipoprotein assessment including triglycerides, non-HDL cholesterol, and ideally particle-size distribution (NMR lipoprofile or apoB) provides better cardiovascular risk stratification than HDL-C alone. Omega-3 supplementation at therapeutic doses and a lipid panel with triglycerides are the highest-yield interventions.

Interactions

A gene-gene interaction between the LIPC locus and HMGCR (the statin target enzyme) has been documented in multi-ethnic cohorts, with the interaction explaining up to 1.1% additional HDL-C variance. Carriers of LIPC risk alleles who also carry HMGCR variants may have amplified or attenuated HDL effects beyond what either locus predicts independently.

CETP variants (particularly rs708272) interact additively with LIPC variants to raise HDL-C, but studies indicate only the CETP side of the interaction translates to reduced coronary artery disease events — underscoring that the source of elevated HDL (HL reduction versus CETP reduction) carries different cardiovascular implications.

Nutrient Interactions

omega-3 fatty acids increased_need

Genotype Interpretations

What each possible genotype means for this variant.

GG Common Variant Normal

Common hepatic lipase variant — standard cardiovascular risk at this locus

You carry two G alleles at rs4775065, the common form of this LIPC intronic variant. About 50% of people globally share this genotype. The A allele associated with elevated low HDL-C and coronary heart disease risk is absent. Your hepatic lipase function at this genetic position is not specifically implicated in elevated cardiovascular risk. Standard lipid monitoring applies.

AG A Allele Carrier Intermediate

One copy of the LIPC risk variant — elevated susceptibility to low HDL and CHD

The LIPC gene encodes hepatic lipase, which remodels HDL particles at the liver surface — converting large, buoyant HDL2 into smaller, denser HDL3 — and clears IDL and VLDL-remnant particles from circulation. Variants in or near LIPC that reduce hepatic lipase expression preserve large HDL2 (raising measured HDL-C) but simultaneously slow remnant clearance, a dual effect with complex net cardiovascular consequences.

The strong statistical association (P=3.82×10⁻¹⁰) in a 60-gene candidate-gene study suggests this is a genuine functional or LD-tagged signal, not a chance finding. Its residual significance after lipid adjustment points to mechanism beyond lipid levels alone — possibly affecting plaque stability, endothelial function, or post-prandial lipoprotein dynamics.

AA A Allele Homozygous High Risk

Two copies of the LIPC risk variant — highest genetic susceptibility at this locus

Homozygous AA individuals carry the maximum genetic burden at this LIPC locus. While the heterozygote OR (2.36) was more precisely estimated than the homozygote OR (1.54, 95% CI 0.82–2.89) due to the smaller number of AA homozygotes in the study population, the 2df genotypic test combining all three genotypes reached P=3.82×10⁻¹⁰, capturing the overall risk gradient. The lipid-adjusted P-value of 1.15×10⁻⁶ confirms risk contribution independent of measured HDL-C and triglycerides.