rs17514846 — FURIN

Intronic regulatory variant modulating FURIN expression via allele-specific DNA methylation, associated with coronary artery disease risk and blood pressure through macrophage and endothelial cell mechanisms

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FURIN: The Cardiovascular Protein Factory

Every bioactive peptide in your body starts life as an inactive precursor — a pro-protein that must be cleaved into its functional form. FURIN (also called PCSK311 PCSK3
proprotein convertase subtilisin/kexin type 3) is one of the most important enzymes responsible for these cuts. Its substrates include pro-BNP and pro-ANP22 pro-BNP and pro-ANP
heart-secreted hormones that lower blood pressure and reduce fluid retention, pro-renin33 pro-renin
the inactive form of renin, the first enzyme in the blood-pressure- raising renin-angiotensin-aldosterone cascade, pro-endothelin-1, and pro-TGF-β. Essentially, FURIN sits at the top of multiple cardiovascular control systems simultaneously. The variant rs17514846, located in an intron of the FURIN gene on chromosome 15q26.1, alters how much of this enzyme is produced — with consequences for both coronary artery disease risk and blood pressure regulation.

The Mechanism

The rs17514846 variant operates through allele-specific epigenetic regulation44 allele-specific epigenetic regulation
the same DNA sequence making different amounts of protein depending on chemical marks attached to it. The C allele contains a CpG dinucleotide — a sequence prone to methylation — directly at the variant position. When methylated, this CpG recruits the transcription repressor MeCP255 MeCP2
methyl-CpG-binding protein 2, a protein that binds methylated DNA and turns off nearby genes, which silences FURIN expression. The A allele, by contrast, destroys the CpG motif entirely — there is nothing to methylate, nothing to recruit MeCP2, and FURIN expression remains higher. Researchers confirmed this by treating C/C cells with a DNA methylation inhibitor, which increased FURIN expression to A/A levels.

In macrophages66 macrophages
immune cells that accumulate in atherosclerotic plaques and are central to plaque development, higher FURIN from the A allele drives three pro-atherogenic behaviors: increased migration into arterial walls, faster proliferation, and reduced programmed cell death. The same phenomenon occurs in vascular endothelial cells77 vascular endothelial cells
the cells lining artery walls that control what enters and exits the vessel wall: A-allele carriers show higher FURIN expression, elevated endothelin-1 (a potent vasoconstrictor), activated NF-κB signaling, more VCAM-1 and MCP-1, and greater monocyte adhesion and transendothelial migration — all hallmarks of early atherosclerosis.

The Evidence

The association between the chromosome 15q26.1 locus and coronary artery disease was first robustly established in GWAS meta-analyses through the CARDIoGRAMplusC4D consortium88 CARDIoGRAMplusC4D consortium
a mega-consortium pooling CAD genetic data from hundreds of thousands of individuals. The A allele confers approximately 1.04–1.07-fold increased CAD risk99 1.04–1.07-fold increased CAD risk
a modest individual OR but important population-level effect given the high allele frequency. In the Bruneck Study, A-allele carriers showed higher circulating MCP-1 and greater carotid intima-media thickness1010 higher circulating MCP-1 and greater carotid intima-media thickness
two established intermediate biomarkers on the path to clinical heart disease.

The blood pressure dimension involves a related but partially independent mechanism. The ICBP/Global BPgen consortium GWAS in 200,000 Europeans1111 The ICBP/Global BPgen consortium GWAS in 200,000 Europeans
Ehret et al., Nature 2011 identified the FURIN-FES locus among those with genome-wide significant associations with systolic and diastolic blood pressure. The biology is consistent: when FURIN processes pro-BNP and pro-ANP into their active natriuretic forms, blood pressure falls. When FURIN processes pro-renin receptor (PRR) to regulate RAAS activity, blood pressure is modulated from the other direction. Higher FURIN from the A allele therefore activates intersecting vasodilatory and vasoconstrictive pathways simultaneously — net effect depends on tissue context and disease stage.

A Japanese cohort study found A-allele carriers had significantly lower triglycerides and higher HDL, suggesting metabolic syndrome protection in that population — an apparently paradoxical protective metabolic effect coexisting with elevated CAD risk through the vascular biology pathway.

Practical Actions

For A-allele carriers, the elevated atherosclerosis biology argues for aggressive management of all modifiable cardiovascular risk factors — not because of generic health advice, but because the genetic burden this variant adds is magnified by other risk factors. Specifically: measuring carotid intima-media thickness (CIMT) provides a direct readout of the subclinical atherosclerosis this variant promotes, and early detection allows intervention before clinical events occur. The inflammation axis (elevated MCP-1, VCAM-1, endothelin-1) makes high-sensitivity CRP a particularly informative biomarker for this genotype.

Carriers of two A alleles (AA genotype, approximately 23% globally) bear the greatest FURIN elevation and the highest cumulative risk. For them, cardiac screening conversations with a physician — including coronary calcium scoring when age-appropriate — are warranted earlier than population guidelines suggest.

Interactions

The rs17514846 locus includes several SNPs in high linkage disequilibrium — rs6224, rs11372849, and rs8039305 — that may contribute additional regulatory effects. The cis-eQTL variant rs47021212 rs4702
a FURIN 3'-UTR variant associated with both blood pressure and schizophrenia risk appears in partial LD with rs17514846 and affects FURIN expression through a distinct molecular mechanism, suggesting additive effects in individuals carrying both. There are no well-characterized interactions with other SNPs already in this database, but FURIN's broad substrate range means variants in RAAS genes (AGT rs699, AGTR1 rs5186) that affect the same blood pressure pathways could compound cardiovascular risk in a clinically meaningful way.

Genotype Interpretations

What each possible genotype means for this variant.

CC Standard FURIN Expression Normal

Normal FURIN expression; lowest CAD risk at this locus

You carry two copies of the C allele. The methylated CpG motif at rs17514846 recruits MeCP2, partially suppressing FURIN expression to normal levels. This is associated with lower coronary artery disease risk compared to A-allele carriers. About 27% of people globally share this genotype, with higher prevalence in East Asian populations (~71%).

AC Elevated FURIN Expression Intermediate

One risk allele — moderately elevated FURIN expression and CAD risk

The heterozygous state means you have one copy of each regulatory variant. Your FURIN expression sits between CC and AA levels — partial suppression from the methylated C allele, partial elevation from the unmethylated A allele. In macrophages, this translates to moderately increased capacity for macrophage migration and reduced apoptosis, both of which contribute to atherosclerotic plaque accumulation. In endothelial cells, elevated endothelin-1 and VCAM-1 create a mildly pro-inflammatory vascular environment. The effect is real but modest — this variant contributes one of many genetic inputs to cardiovascular risk and should be interpreted in the context of lipid profile, blood pressure, inflammation markers, and lifestyle.

AA High FURIN Expression High Risk

Two risk alleles — highest FURIN expression and greatest CAD risk at this locus

The homozygous A/A state removes both copies of the CpG methylation site, meaning FURIN is transcribed without methylation-mediated suppression on either allele. CRISPR-validated experiments confirm that isogenic A/A cells produce substantially more FURIN protein than C/C cells. The downstream consequences span three converging pathways: (1) macrophage biology — more migration, proliferation, and survival in arterial walls promotes plaque growth; (2) endothelial inflammation — elevated endothelin-1, VCAM-1, MCP-1, and NF-κB activity creates a vascular surface that attracts monocytes and accelerates lesion formation; (3) hemodynamic effects — altered processing of pro-BNP, pro-ANP, and pro-renin receptor through the RAAS and natriuretic peptide axes contributes to blood pressure dysregulation. The A/A genotype represents the full expression of this locus's cardiovascular risk profile.