rs35257264 — ST3GAL4

ST3GAL4 — The Sugar Coat That Keeps Clotting Factors in Circulation

Your blood carries von Willebrand factor (VWF)¹¹ von Willebrand factor (VWF)
A large multimeric protein that anchors platelets to damaged vessel walls and escorts Factor VIII through the circulation; elevated VWF is an independent VTE risk factor and Factor VIII continuously, but the liver clears these proteins at a rate that determines their plasma concentration. What regulates clearance? In large part, a molecular sugar coating. Sialic acid residues attached to the outer glycan chains of VWF and Factor VIII shield them from asialoglycoprotein receptors (ASGPR) on hepatocytes — the liver's galactose-recognition machinery that flags aging or under-glycosylated proteins for destruction. The ST3GAL4 enzyme is responsible for adding α2,3-linked sialic acids to these protective glycan termini. Variants near the ST3GAL4 gene alter this sialylation activity, which in turn shifts steady-state VWF and Factor VIII levels — and therefore VTE risk.

The Mechanism

ST3GAL4 (ST3 beta-galactoside alpha-2,3-sialyltransferase 4)²² ST3GAL4 (ST3 beta-galactoside alpha-2,3-sialyltransferase 4)
One of a family of six ST3GAL enzymes that catalyze transfer of sialic acid in the α2,3 linkage onto N- and O-linked glycans is expressed in endothelial cells and hepatocytes, where it acts on newly synthesized VWF and Factor VIII. Fully sialylated VWF has reduced affinity for ASGPR on liver macrophages and hepatocytes; removing sialic acid from VWF dramatically accelerates its hepatic clearance³³ removing sialic acid from VWF dramatically accelerates its hepatic clearance
Byrne et al. 2025 showed that enzymatic desialylation of both plasma-derived and recombinant VWF produced identical, rapid clearance regardless of other glycan differences.

The rs35257264 T allele is located in an intronic region overlapping the ST3GAL4 genomic locus. It acts as a cis-regulatory variant — most likely influencing ST3GAL4 expression or splicing in endothelial cells — rather than altering the enzyme's amino acid sequence directly. The net effect of the T allele is an upward shift in steady-state sialylation activity, meaning VWF and Factor VIII are more effectively protected from clearance, circulate longer, and accumulate at higher plasma concentrations. The coagulation balance tilts toward clotting.

The Evidence

The VWF/FVIII-elevating effect of ST3GAL4 variants was established in a 2016 ARIC cohort analysis: Song et al. studied 12,117 participants⁴⁴ Song et al. studied 12,117 participants
Multi-ethnic ARIC cohort; associations held in both European American and African American ancestry groups after adjustment for ABO blood group, age, BMI, hypertension, and diabetes and identified three ST3GAL4 intronic SNPs significantly associated with both VWF antigen levels and Factor VIII activity.

The VTE connection was subsequently confirmed in two large independent GWAS meta-analyses. Thibord et al. 2022⁵⁵ Thibord et al. 2022
Cross-ancestry meta-analysis of 30 cohorts; 81,669 VTE cases including European, African, and Hispanic ancestry populations; identified 135 independent genomic loci identified the ST3GAL4 region among 135 independent VTE risk loci. Ghouse et al. 2023⁶⁶ Ghouse et al. 2023
Nature Genetics; 81,190 VTE cases and 1,419,671 controls across six cohorts; 93 significant loci, 62 previously unreported; polygenic risk score performance comparable to monogenic thrombophilia testing replicated the ST3GAL4 region in a non-overlapping cohort with 93 total loci, confirming it as a reproducible signal.

A 2024 GWAS of 45,289 participants for circulating Factor VIII and VWF levels⁷⁷ circulating Factor VIII and VWF levels
de Vries et al. 2024; identified 7 novel loci for FVIII including ST3GAL4 at genome-wide significance P < 5×10⁻⁹ identified ST3GAL4 as a novel genome-wide significant locus for Factor VIII levels, closing the mechanistic loop between the GWAS VTE signal and the VWF/FVIII axis.

For clinical context: a systematic review and meta-analysis of 15 studies⁸⁸ a systematic review and meta-analysis of 15 studies
Lowe et al. 2023; 5,327 VTE cases; pooled OR for FVIII quartile 4 vs. quartile 1: 3.92 (95% CI 1.61–5.29) found that Factor VIII levels above the 90th percentile are associated with a 3-fold higher VTE risk, confirming that elevated FVIII — the proximal mechanism by which ST3GAL4 T allele exerts its effect — is a dose-dependent independent VTE risk factor.

The effect size for rs35257264 itself is modest (OR approximately 1.21 per T allele), which is typical for common regulatory GWAS variants acting through quantitative trait changes. This places it in the context of a contributing factor rather than a high-penetrance thrombophilia like Factor V Leiden or prothrombin G20210A.

Practical Implications

The T allele's relevance is highest when added to other thrombotic risk — surgery, immobility, oral contraceptives, pregnancy, or co-inherited thrombophilias. In these settings, the additional nudge toward elevated VWF/FVIII that the T allele provides compounds with environmental and genetic co-factors. Carriers should ensure providers are aware of this variant when planning high-risk situations, and may benefit from VWF or Factor VIII level testing to understand their baseline quantitative risk.

There are no drugs or supplements that specifically modulate ST3GAL4 activity in clinical practice. Standard VTE prevention measures apply with heightened attention to provocation management.

Interactions

The ST3GAL4 T allele acts through the same VWF/FVIII quantitative axis as other clotting factor loci. Its effect is most clinically relevant when combined with other thrombophilic variants — particularly [Factor V Leiden (rs6025, F5 R506Q) | Activated protein C resistance; ~5% carrier frequency in Europeans; 3-8 fold VTE risk for heterozygotes] or [prothrombin G20210A (rs1799963) | ~1-3% carrier frequency; 2-5 fold VTE risk], which impair anticoagulant mechanisms at a different node of the coagulation cascade. Combined carrier status for ST3GAL4 T allele plus either classical thrombophilia would compound risks additively or possibly synergistically.

ABO blood group is a critical co-determinant of VWF levels: blood group O individuals have ~25% lower VWF than non-O individuals through a separate glycosylation-clearance mechanism. The ST3GAL4 T allele effect operates independently of ABO (Song et al. 2016 adjusted for ABO) but their absolute VWF levels are determined by both factors together.