rs35136575 — APOC1P1 HCR-2 Enhancer Variant

The APOE Locus Enhancer That Fine-Tunes Your Cholesterol

Roughly 27 kilobases downstream of the APOE gene¹¹ APOE gene
Apolipoprotein E — a key cholesterol transport protein that determines how quickly LDL is cleared from the bloodstream lies a compact enhancer element called HCR-2²² HCR-2
Hepatic Control Region 2 — a liver-specific regulatory DNA sequence that boosts transcription of the entire APOE/C1/C4/C2 gene cluster. Most genetic research on chromosome 19q13 focuses on the famous APOE ε2/ε3/ε4 isoforms (rs429358, rs7412), which differ in protein sequence. The rs35136575 variant operates one level upstream: it changes how much apoE protein the liver makes in the first place, independent of which APOE isoform you carry.

The Mechanism

HCR-2 is a 319-base-pair regulatory element that shares 85% sequence identity with HCR-1, the primary hepatic enhancer of the APOE cluster. Together they drive liver-specific expression of APOE, APOC1, APOC2, and APOC4 — the apolipoprotein genes that assemble and remodel the VLDL and HDL particles circulating in your bloodstream. The rs35136575 C>G substitution sits within footprint region 1b of HCR-2, a conserved sequence that binds transcription factors including SP1, HNF-3, C/EBP, and nuclear receptors³³ including SP1, HNF-3, C/EBP, and nuclear receptors
Zannis et al. identified these binding proteins in the HCR-1/HCR-2 regulatory system. The G allele appears to reduce the efficiency of this binding, dampening hepatic apoE output. Because the liver is the primary source of plasma apoE — and because apoE concentration correlates directly with LDL particle remodeling — lower hepatic apoE production translates into modestly lower circulating LDL cholesterol.

The Evidence

Klos et al. (2008)⁴⁴ Klos et al. (2008)
Klos et al. APOE/C1/C4/C2 hepatic control region polymorphism influences plasma apoE and LDL cholesterol levels. Hum Mol Genet, 2008 sequenced 102 kb of the APOE locus in 1,943 White and 2,046 African-American participants from the CARDIA study, identifying 115 variants and testing their association with LDL-C and plasma apoE after controlling for the APOE ε2/ε3/ε4 genotype. rs35136575 emerged as the top independent signal. In CARDIA Caucasians, mean LDL-C fell dose-dependently across genotypes: CC 110.4 mg/dL → CG 106.8 mg/dL → GG 101.7 mg/dL (P = 0.0004, accounting for ~1% of LDL-C variance). The association replicated in ARIC Caucasians (n = 10,427; P = 0.0065). Crucially, plasma apoE protein levels fell significantly with increasing G allele copies in all three GENOA populations — White (CC 5.44 → GG 4.41 mg/dL), African-American (CC 5.41 → GG 4.74 mg/dL), and Mexican-American (CC 5.61 → GG 4.36 mg/dL) — all P ≤ 0.002. This multi-ethnic replication of the apoE-lowering effect confirms that the variant acts through hepatic gene regulation, not through linkage with APOE isoform variants.

A separate study in growth hormone-deficient adults (n = 318; Barbosa et al. 2012⁵⁵ Barbosa et al. 2012
Barbosa et al. Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults. Eur J Endocrinol, 2012) found that G allele carriers had lower serum triglycerides at baseline, suggesting the HCR-2 variant influences the full spectrum of apolipoprotein- mediated lipoprotein metabolism — not only LDL-C.

Large proteomics GWAS data further confirm a robust association between rs35136575 and circulating apolipoprotein E protein levels (beta −0.228 SD units; P = 2×10⁻¹¹), consistent with the regulatory mechanism identified in the Klos functional study.

Practical Actions

The LDL-lowering effect of the G allele (approximately 5–9 mg/dL per copy) is modest in isolation but adds meaningfully to the overall cardiovascular risk picture — especially when combined with APOE isoform status (rs429358, rs7412) and other lipid-pathway variants. G allele carriers who also carry the APOE ε3/ε3 genotype benefit most, as neither variant independently elevates risk. For CC homozygotes (the majority), standard cardiovascular prevention applies, but their slightly higher plasma apoE warrants particular attention to saturated fat intake, since apoE mediates uptake of saturated fat-rich remnant particles into the liver.

Interactions

This variant operates in the same genomic neighborhood as the two defining APOE isoform SNPs (rs429358 — E4 determinant; rs7412 — E2 determinant). The Klos study explicitly controlled for APOE ε2/ε3/ε4 status, confirming rs35136575 is an independent signal — not simply a proxy for E4 or E2. A person who carries both APOE ε4 (rs429358 CC) and the HCR-2 CC genotype faces additive LDL elevation from both higher apoE concentration and impaired LDL receptor binding. Conversely, an APOE ε4 carrier who also has the HCR-2 GG genotype enjoys partial offsetting — lower hepatic apoE output attenuates but does not eliminate the E4 LDL-raising effect.