rs11220465 — ST3GAL4 ST3GAL4 VWF/FVIII Modifier

Common intronic variant in the ST3GAL4 sialyltransferase gene associated with modestly elevated VWF antigen and Factor VIII activity levels; the A allele impairs sialic acid capping of these clotting proteins, slowing their hepatic clearance and raising plasma concentrations

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ST3GAL4 rs11220465 — The Common Sialyltransferase Variant That Nudges Clotting Factor Levels

Every protein in your blood has a molecular expiration date stamped on its surface as a sugar code. Von Willebrand factor (VWF)11 Von Willebrand factor (VWF)
A large multimeric glycoprotein that anchors platelets to damaged vessel walls and carries Factor VIII through the circulation; plasma level is a major determinant of clotting tendency and Factor VIII (FVIII)22 Factor VIII (FVIII)
The cofactor in the intrinsic coagulation pathway; the two molecules circulate as a non-covalent complex and their plasma levels are tightly correlated both carry a coating of sialic acid residues on their glycan chains. When these sialic acids are intact, the proteins circulate freely. When they are absent or reduced, galactose residues on the protein surface become exposed and the liver's asialoglycoprotein receptors (ASGPR) recognize them as disposal targets — pulling them out of circulation. The ST3GAL4 enzyme determines how thoroughly this protective sialic acid coat is applied. Variants in its first intron, including rs11220465, tune this activity up or down in ways that directly shift the steady-state plasma levels of VWF and FVIII.

The Mechanism

ST3GAL4 (ST3 beta-galactoside alpha-2,3-sialyltransferase 4)33 ST3GAL4 (ST3 beta-galactoside alpha-2,3-sialyltransferase 4)
One of the six ST3GAL family enzymes; acts in the Golgi apparatus to transfer sialic acid onto galactose residues at the termini of N- and O-linked glycan chains is expressed in endothelial cells (where VWF is synthesized and secreted) and hepatocytes. rs11220465 is an intronic variant located in the first intron of the ST3GAL4 gene at chr11:126387884 (GRCh38). It does not alter the enzyme's amino acid sequence. Instead, it sits in a regulatory region that likely contains transcription factor binding sites — bioinformatic analysis of the region identifies multiple regulatory motifs whose affinity changes with the A allele. The downstream consequence is a modest shift in ST3GAL4 activity that alters how completely VWF and FVIII are sialylated before secretion.

The causal mouse model is compelling: Ellies et al. 200244 Ellies et al. 2002
Knockout mice lacking ST3Gal-IV have plasma VWF levels approximately 50% of normal; intravenous asialofetuin (which competes for ASGPR binding sites) restores VWF half-life, directly demonstrating that ASGPR-mediated clearance of under-sialylated VWF is the mechanism. In humans, the A allele at rs11220465 appears to reduce effective sialylation rather than eliminate it, producing a quantitatively milder but directionally consistent shift toward faster VWF/FVIII clearance and lower steady-state levels. This is the opposite direction from the rarer rs35257264 T allele (which increases sialylation and raises VWF/FVIII) — an important contrast since both variants act at the same locus via the same enzyme.

The Evidence

The definitive human genetic study is Song et al. 201655 Song et al. 2016
Analysis of 12,117 participants from the multi-ethnic Atherosclerosis Risk in Communities (ARIC) cohort; associations tested for 14 ST3GAL4 SNPs against VWF antigen and FVIII activity; adjustment for age, sex, BMI, hypertension, diabetes, ever-smoking status, and ABO blood group. Among three ST3GAL4 intronic SNPs associated with both VWF and FVIII, rs11220465 showed a VWF difference of approximately 10% between GG homozygotes (mean ~99% of normal) and AA homozygotes (mean ~109%), and was significantly associated with FVIII activity after full covariate adjustment (p=0.0002).

The VWF and FVIII association with VTE risk is well-documented in epidemiological data. Rietveld et al. 201966 Rietveld et al. 2019
Case-control study; 2,377 venous thrombosis cases and 2,940 controls; tested eight coagulation factors; VWF and FVIII showed by far the strongest associations with VTE among all factors tested found that VWF above the 99th percentile carries an OR of 24.0 (95% CI 15.3–37.3) for VTE, and FVIII an OR of 23.0 — the strongest associations among all coagulation factors studied. Edvardsen et al. 202177 Edvardsen et al. 2021
Prospective cohort with incident VTE events; dose-response analysis across quartiles; strongest association seen for unprovoked VTE and DVT found a dose-dependent VTE risk across VWF quartiles: highest vs. lowest quartile OR 1.45 overall (95% CI 1.03–2.03), rising to OR 2.74 (95% CI 1.66–4.54) for unprovoked VTE.

For rs11220465 specifically, the effect on VWF/FVIII is modest — roughly 5–10% per A allele at the population mean level — placing it solidly in the moderate rather than strong evidence tier for direct thrombosis risk prediction. The variant is nonetheless clinically informative as part of a cumulative VWF/FVIII risk picture, particularly when VWF or FVIII levels are elevated on direct measurement.

Practical Actions

Because the A allele's effect operates through quantitative elevation of VWF and FVIII, the most actionable step is to measure these proteins directly to determine whether your levels fall in a clinically elevated range. The ~10% shift seen between GG and AA homozygotes can combine with other factors — ABO blood type (non-O individuals already have ~25% higher VWF), oral contraceptive use, obesity, and age — to push total VWF into the range where VTE risk becomes clinically significant.

Co-inherited thrombophilic variants (Factor V Leiden rs6025, prothrombin G20210A rs1799963) act through mechanistically independent pathways and their effects are additive with VWF/FVIII elevation. If you also carry rs35257264 T allele (the rarer, sialylation-upregulating ST3GAL4 variant), both operate at the same locus but may show some non-additivity depending on haplotype structure.

Interactions

rs11220465 clusters within ~4 kb of rs2186717 and rs7928391 in the first intron of ST3GAL4 (Song et al. 2016). These three variants were identified as distinct signals — rs11220465 was not in perfect linkage disequilibrium with the other two, suggesting it may tag a partially independent regulatory element. The nearby rs35257264 (chr11:126426921) is a rarer variant (~2% MAF in Europeans) at a different intronic position with stronger per-allele effects and direct replication in VTE GWAS meta-analyses.

ABO blood type is the dominant genetic modifier of VWF levels; non-O blood groups inhibit VWF clearance through a separate mechanism and raise VWF approximately 25% above blood group O levels. The ST3GAL4 rs11220465 effect was confirmed independent of ABO in the Song et al. analysis, meaning both effects contribute additively to total VWF level.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal VWF/FVIII Sialylation Normal

Reference genotype — ST3GAL4 sialylation at population baseline

You carry two copies of the G reference allele at rs11220465. Your ST3GAL4 sialylation activity is at the population baseline for this variant, meaning VWF and Factor VIII receive the typical degree of sialic acid protection and are cleared from circulation at a normal rate. This is the most common genotype globally, found in approximately 64% of people worldwide and about 70% of Europeans. You do not carry the A allele that has been associated with modestly elevated VWF and FVIII levels from this locus.

AG Mildly Elevated VWF/FVIII Intermediate

One A allele — modest elevation of VWF and Factor VIII from impaired sialylation

The A allele at rs11220465 is an intronic regulatory variant rather than a protein-coding change. It acts on the first intron of ST3GAL4, a sialyltransferase that adds protective sialic acid residues to the glycan chains of VWF and FVIII in endothelial cells and hepatocytes. With one A allele, the sialylation activity of ST3GAL4 is partially reduced, exposing more galactose residues on VWF and FVIII that trigger asialoglycoprotein receptor (ASGPR) recognition and hepatic clearance. Less efficient clearance protection means slightly higher circulating concentrations.

In epidemiological context: VWF above the 99th percentile carries an OR of 24.0 for VTE (Rietveld et al. 2019), though this applies to extreme elevation rather than the modest shift this variant produces. A dose-dependent VTE risk across quartiles has been observed (Edvardsen et al. 2021), confirming that even sub-extreme elevations contribute to risk. The rs11220465 A allele's contribution is additive with other VWF-raising factors including non-O ABO blood type and with mechanistically distinct thrombophilias like Factor V Leiden.

AA Moderately Elevated VWF/FVIII High Risk

Two A alleles — maximal effect from this variant on VWF and Factor VIII elevation

With two A alleles, both copies of your ST3GAL4 regulatory region carry the variant associated with impaired sialylation efficiency. The enzyme's activity modification is at its maximum for this locus, and the resulting partial reduction in α2,3-linked sialic acid coverage on VWF and FVIII glycan chains exposes more galactose termini to hepatic asialoglycoprotein receptors (ASGPR). The consequence is a persistent slight upward shift in steady-state VWF and FVIII plasma concentrations.

The clinical significance is proportional to your absolute levels. If your VWF antigen already runs high for other reasons (non-O blood group, obesity, age, or chronic inflammation), this variant's ~10% additive contribution may push you into clinically elevated territory. VWF and FVIII are the two coagulation factors most strongly associated with VTE risk — elevated VWF above the 99th percentile carries an OR of 24 for VTE (Rietveld et al. 2019), and even highest vs. lowest quartile comparison shows OR 1.45 for any VTE and OR 2.74 for unprovoked VTE (Edvardsen et al. 2021).

Co-inherited thrombophilias (Factor V Leiden, prothrombin G20210A) act through independent coagulation pathway nodes and their effects on VTE risk are additive with elevated VWF/FVIII.