rs12593008 — LIPC

Intronic LIPC variant in intron 1 associated with low HDL risk, predominantly in women; the C allele is the risk allele for reduced HDL-cholesterol levels

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LIPC rs12593008 — Intron 1 Variant and Sex-Specific HDL Risk

Hepatic lipase (HL), the enzyme encoded by the LIPC gene on chromosome 15q21-22, governs the final stage of lipoprotein particle remodeling in the liver. It hydrolyzes triglycerides and phospholipids from HDL2, converting the large, buoyant particles into smaller, denser HDL3 — the form most capable of capturing cholesterol from arterial walls. HL also clears intermediate-density lipoprotein (IDL) and triglyceride-rich VLDL remnants. The net result is that HL activity shapes not just your total HDL-cholesterol number but the composition and functional quality of those particles. The LIPC locus is among the most consistently replicated GWAS signals for HDL-cholesterol in the human genome.

rs12593008 is located in intron 1 of LIPC (GRCh38 chr15:58,468,776, C>A).

The Mechanism

Sex hormones modulate hepatic lipase expression directly — estrogen suppresses HL activity and testosterone stimulates it.

The Evidence

The primary association for rs12593008 itself comes from a family-based linkage and association study by Feitosa et al. (2009)11 Feitosa et al. (2009), which examined 19 tag-SNPs across ~140 kb of the LIPC locus in 591 families (2,238 subjects) from the NHLBI Family Heart Study. The intron 1 SNP rs12593008 showed strong sex-specific association: in women, the A allele (AC or AA genotypes) was associated with a significantly decreased risk of low HDL (p=0.00217, q=0.0412 by TRANSMIT; p=0.02461 by FBAT). The effect was weaker and non-significant in men. A related promoter SNP, rs261342, showed the strongest absolute effect in women — the less common allele associated with ~14% higher HDL-C and ~30% lower risk of low HDL.

The broader LIPC locus context is well established. The Teslovich et al. 2010 Nature meta-analysis22 Teslovich et al. 2010 Nature meta-analysis of more than 100,000 Europeans identified the LIPC region as a genome-wide significant HDL-C locus. A Mendelian randomization analysis by Silbernagel et al. (2019)33 Mendelian randomization analysis by Silbernagel et al. (2019) found that lower hepatic lipase activity causally increases cardiovascular risk, with individuals in the highest LDL-triglyceride quintile (a read-out of HL impairment) showing a hazard ratio of 2.53 for cardiovascular mortality compared to the lowest quintile (9.9-year follow-up, p<0.001).

Nutrient Interactions

saturated fat altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

AA Protective Genotype Beneficial

Two copies of the protective A allele; lowest risk of low HDL at this locus

You carry two A alleles at rs12593008. This genotype is present in about 6% of people of European descent. In the NHLBI Family Heart Study, the A allele (in either one or two copies) was associated with significantly reduced risk of low HDL, with the effect being strongest in women. Your genotype at this locus does not contribute to low-HDL risk.

AC Intermediate HDL Protection Intermediate

One A allele provides partial protection against low HDL

The sex-specific signal at rs12593008 is stronger in women than men.

CC Low-HDL Risk Genotype High Risk

Two C alleles — highest risk genotype for low HDL at this LIPC locus, especially in women

The CC genotype lacks the A allele that was found protective in the Feitosa 2009 family study (p=0.00217 in women).

The sex-specific finding is important: the association was strongest in women in the primary study.