rs1800380 — VWF Arg960= (synonymous)

Common synonymous variant in the VWF D2/D' domain region; the T allele is part of a haplotype block strongly associated with elevated plasma VWF antigen levels, increasing platelet adhesion efficiency and thrombotic risk, while the C allele is associated with lower circulating VWF

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VWF Arg960= — A Synonymous Variant That Speaks Through Its Haplotype

Von Willebrand factor11 Von Willebrand factor
a large multimeric glycoprotein produced by endothelial cells and megakaryocytes; acts as the primary platelet adhesion bridge at sites of vascular injury and as the plasma carrier that protects coagulation factor VIII from premature degradation is arguably the single most important quantitative determinant of bleeding and thrombosis risk below the level of frank coagulation factor deficiency. Normal-range plasma VWF antigen levels span roughly 50–200 IU/dL — a four-fold window — and that variation is substantially heritable. The rs1800380 variant falls within a 50-kilobase stretch of the VWF gene that has the strongest known cis-acting influence on circulating VWF concentrations in people of European and African descent.

The Mechanism

rs1800380 is a synonymous C>T substitution in VWF exon 22 (c.2880G>A; NM_000552.5) that does not change the encoded amino acid — both the C and T alleles produce arginine at codon 960. The T allele is on the GRCh38 plus strand; the VWF gene is on the minus strand, so this corresponds to a c.2880G>A coding-strand change (G→A) that is silent at the protein level. Yet the variant strongly associates with plasma VWF antigen levels across independent populations.

The likely explanation is that rs1800380 itself is not the causative change but rather a tag SNP22 tag SNP
a variant in strong linkage disequilibrium with the true functional variant, allowing it to serve as a reliable proxy for the causal haplotype in GWAS. It sits within haplotype block 533 haplotype block 5
a 50-kb stretch of the VWF gene encoding the D2, D', and D3 domains that regulate VWF multimerization, packaging into Weibel-Palade bodies, and regulated secretion into the circulation. The T allele marks the high-VWF haplotype in this block. The causal variant — likely within the same block — may alter VWF mRNA secondary structure, splicing efficiency, transcription factor binding, or protein folding in the secretory pathway.

The effect of the T allele is additive: each copy adds approximately +0.03 units (log-scale) to circulating VWF:Ag after adjustment for ABO blood group, and the p-value for this association is 4.4×10⁻⁹ post-ABO adjustment in the ARIC cohort (n=7,856). This level of evidence is genome-wide significant and replicates across European and African-descent populations.

The Evidence

The definitive mapping of rs1800380 to VWF antigen levels comes from the ARIC cohort target-gene analysis44 ARIC cohort target-gene analysis
Campos et al. Blood 2011, 7,856 European-descent subjects, 78 VWF SNPs analyzed. Of 18 SNPs significantly associated with VWF:Ag in this dataset, rs1800380 was one of only two in actual exonic positions (the other being rs1063857 in exon 18). The pre-ABO p-value was 1.6×10⁻⁷; after ABO adjustment the signal strengthened to 4.4×10⁻⁹, confirming that the haplotype's VWF-raising effect is mechanistically independent of blood-group-mediated VWF clearance. The 15 significant block-5 and block-6 SNPs form two distinct haplotypes that together explain a substantially larger fraction of within-gene VWF level variance than any single SNP alone.

The downstream clinical consequence of elevated VWF is well established. A transethnic GWAS meta-analysis by Sabater-Lleal et al. 201955 Sabater-Lleal et al. 2019 used Mendelian randomization to demonstrate a causal relationship between plasma VWF levels and ischemic stroke risk — meaning that genetically elevated VWF is not merely a marker of vascular inflammation but a driver of thrombotic events. This finding upgrades the clinical relevance of VWF-raising variants from "associated with higher biomarker" to "causally linked to stroke," at least at the population level.

Plasma VWF levels above 150 IU/dL are associated with 2–3× increased risk of venous thromboembolism in longitudinal studies (Vischer 2011)66 (Vischer 2011). The VWF-raising haplotype tagged by rs1800380 T shifts baseline VWF in the direction of this elevated-risk zone, particularly in non-O blood group individuals (who already have slower VWF clearance due to O-type glycan differences).

In the Rotterdam Study's promoter analysis (de Lange et al. 2004)77 (de Lange et al. 2004), a promoter haplotype associated with higher VWF levels showed a 2.6-fold increased coronary heart disease risk in subjects with advanced atherosclerosis — illustrating how the VWF-raising effect becomes most clinically relevant in the setting of other vascular risk factors.

The evidence level is strong: the rs1800380 T allele association with VWF:Ag levels reaches genome-wide significance, replicates across ancestries, and the downstream cardiovascular consequences of elevated VWF have causal support from Mendelian randomization. The individual effect size is modest (explaining <1% of VWF variance on its own), and the haplotype context means the variant's specific contribution cannot be fully disentangled from neighboring SNPs without fine-mapping.

Practical Actions

For TT homozygotes carrying two copies of the high-VWF haplotype tag, the priority is knowing whether your circulating VWF:Ag is actually elevated — only a blood test can confirm this. Levels persistently above 150 IU/dL (particularly in non-O blood group individuals) warrant proactive monitoring and risk factor management. The pro-thrombotic risk is most relevant in specific, high-stakes contexts: prolonged immobility, major surgery, use of estrogen-containing contraceptives, or concurrent inherited thrombophilia.

CT heterozygotes have intermediate VWF levels and a proportionally intermediate risk profile; measurement is useful if other thrombotic risk factors are present.

CC homozygotes carry the lower-VWF haplotype and have no elevation-specific action items; their VWF levels are in the population-normal to low-normal range for this variant.

Interactions

ABO blood group is the dominant modifier of plasma VWF levels in all populations, accounting for ~15% of VWF antigen variance via glycan-mediated differences in clearance rate. Non-O individuals with the T allele haplotype will show the largest VWF elevations — the high-expression haplotype (tagged by T) combined with non-O blood group (slower VWF clearance) acts in the same direction, compounding VWF elevation above either factor alone.

Among VWF coding variants, rs216311 (Thr1381Ala, exon 28) independently raises VWF levels through a structural mechanism in the D4 domain. Carriers of both the rs1800380 T haplotype and the rs216311 C allele (Ala) will have the highest within-gene VWF levels. The ADAMTS13 substrate-cleavage variants in this category (rs28647808, rs2288904) operate through a complementary VWF-processing pathway: reduced ADAMTS13-mediated VWF cleavage amplifies whatever VWF is being secreted, so high secretion (rs1800380 T haplotype) combined with reduced cleavage (ADAMTS13 variants) further elevates ultra-large VWF multimers.

Genotype Interpretations

What each possible genotype means for this variant.

CC Lower VWF Haplotype Normal

Homozygous for the lower-VWF haplotype — plasma VWF in the population-normal to lower-normal range for this variant

You carry two copies of the C allele at rs1800380, marking the lower-VWF haplotype at this position. The ARIC cohort analysis showed that CC homozygotes have the lowest VWF antigen levels among the three genotypes at this locus. This is the more common genotype globally (~56% of people). Lower VWF within the normal range reduces platelet adhesion efficiency and factor VIII levels slightly, which in the context of thrombotic risk is a favorable direction. No specific intervention is warranted based on this genotype alone.

CT Intermediate VWF Haplotype Intermediate

One copy of the high-VWF haplotype tag — modestly elevated VWF levels, relevant with additional pro-thrombotic risk factors

You carry one C and one T allele at rs1800380, placing you in an intermediate VWF expression category. Approximately 38% of people of European descent share this genotype. The T allele marks the high-VWF haplotype in block 5 of the VWF gene; one copy produces an additive modest increase in plasma VWF:Ag compared to CC homozygotes. In the absence of additional thrombotic risk factors, this single-copy effect is unlikely to drive clinical events independently, but it becomes relevant in combination with non-O blood group, estrogen use, factor V Leiden, or prolonged immobility.

TT High VWF Haplotype High Risk

Homozygous for the high-VWF haplotype tag — elevated plasma VWF antigen levels associated with increased thrombotic risk

The rs1800380 T allele tags a haplotype block spanning the VWF D2, D', and D3 domains — the region that controls VWF multimerization, storage in Weibel-Palade bodies, and regulated secretion into the circulation. Although the synonymous substitution at codon 960 does not change the protein sequence itself, the haplotype it marks is mechanistically linked to higher VWF secretion or slower VWF clearance. The precise causal variant within the block has not been definitively identified, but the association with VWF:Ag is genome-wide significant and ancestrally consistent.

Plasma VWF levels above 150 IU/dL are associated with a 2–3× increased risk of venous thromboembolism in population studies. For TT homozygotes, particularly those with non-O blood group (which slows VWF clearance through a completely independent glycan mechanism), actual circulating VWF levels may approach or exceed this threshold. The clinical relevance increases sharply in the presence of additional coagulation risk factors: factor V Leiden, prothrombin G20210A, atrial fibrillation, estrogen use, prolonged immobility, or concurrent ADAMTS13 variants that reduce VWF cleavage.

The evidence level is strong: genome-wide significant association from an adequately powered target-gene study, Mendelian randomization causality for VWF→stroke, and biological plausibility of the haplotype mechanism. Individual effect size is modest (each T allele adds ~3% on a log VWF scale), so TT homozygotes are not guaranteed to have clinically elevated VWF — only measurement can confirm this.