rs505922 — ABO ABO blood group tag SNP

ABO Blood Group — The Clotting Risk Hidden in Your Blood Type

The ABO gene on chromosome 9 encodes glycosyltransferase enzymes that attach A or B sugar antigens to the surface of red blood cells and to plasma proteins including von Willebrand factor (VWF)¹¹ von Willebrand factor (VWF)
The primary bridge protein that links platelets to damaged vessel walls and carries Factor VIII in the bloodstream. rs505922 is a well-validated tag SNP sitting in the first intron of ABO; its T allele is in near-perfect linkage disequilibrium with the deletion allele that produces blood group O, while the C allele tags non-O types (A, B, and AB). This makes rs505922 one of the most informative proxies for blood group status available on consumer genotyping arrays. The ABO locus has emerged as the single strongest common genetic determinant of venous thromboembolism²² single strongest common genetic determinant of venous thromboembolism
ABO locus accounts for roughly 30% of the genetic variance in plasma VWF levels and is the most replicated genetic signal in VTE GWAS in the genome.

The Mechanism

Blood group A and B glycosyltransferases add carbohydrate chains to VWF and Factor VIII (FVIII) that slow their clearance from the bloodstream. In group O individuals, the non-functional transferase produces VWF with a shorter plasma half-life³³ shorter plasma half-life
Half-life of 10.0 hours in group O vs 25.5 hours in non-O individuals, explaining the chronically lower VWF levels in O carriers. The practical result: plasma VWF is approximately 25% higher in people with A, B, or AB blood types compared to O, and FVIII tracks VWF closely. Because VWF mediates platelet adhesion at sites of vessel injury and stabilizes FVIII — the key amplifier of the clotting cascade — non-O individuals operate with a persistently more pro-coagulant baseline.

ABO antigens are also expressed on selectins and other endothelial adhesion molecules⁴⁴ selectins and other endothelial adhesion molecules
P-selectin and E-selectin carry ABO antigens; GWAS has identified the ABO locus as the top hit for circulating levels of soluble E-selectin, contributing to a low-grade inflammatory tone in non-O individuals that further promotes plaque formation and arterial thrombosis independent of the VWF/FVIII pathway.

The Evidence

The VTE association is one of the most thoroughly replicated findings in cardiovascular genetics. A meta-analysis of 8 prospective and case-control studies⁵⁵ meta-analysis of 8 prospective and case-control studies
Approximately 30,000 combined participants across European cohorts found a pooled odds ratio of 2.09 (95% CI 1.83–2.38) for VTE in non-O vs O individuals, designating non-O blood group as the most common heritable thrombosis risk factor — more prevalent than Factor V Leiden. When Factor V Leiden is also present, the risks multiply: non-O + Factor V Leiden carriers face a ~23-fold higher VTE risk⁶⁶ non-O + Factor V Leiden carriers face a ~23-fold higher VTE risk
Compared to OO genotype without FVL, far exceeding the ~4.6-fold from FVL alone or ~1.7-fold from non-O alone.

For coronary artery disease, two large prospective cohorts — the Nurses' Health Study and Health Professionals Follow-up Study totaling 89,501 participants — found non-O blood type associated with HR 1.10 (95% CI 1.03–1.18) for incident CHD⁷⁷ non-O blood type associated with HR 1.10 (95% CI 1.03–1.18) for incident CHD
Multivariate-adjusted, accounting for conventional risk factors including blood pressure, cholesterol, smoking, and diabetes. A subsequent meta-analysis of 10 studies (174,945 participants)⁸⁸ meta-analysis of 10 studies (174,945 participants)
Including multiple independent European and Asian cohorts confirmed: non-O OR 1.14 for coronary artery disease and OR 1.16 for acute MI. For stroke, a mega-meta-analysis encompassing 145,499 ischemic stroke cases and over 2 million controls⁹⁹ mega-meta-analysis encompassing 145,499 ischemic stroke cases and over 2 million controls
Largest pooled dataset in the literature to date reported non-O OR 1.13 for ischemic stroke and OR 1.24 for type AB specifically. Across all arterial and venous endpoints, the effect size is modest but remarkably consistent across populations, study designs, and decades of research.

Practical Actions

The elevated baseline clotting tendency from non-O blood type becomes clinically relevant in situations where additional thrombosis risk is layered on top of it. Hormonal contraception (combined oral contraceptives) and hormone replacement therapy raise VTE risk 3–4 fold on their own; in non-O women, this compounds further. Non-O blood type is classified as a haemostatic abnormality equivalent to mild thrombophilia¹⁰¹⁰ Non-O blood type is classified as a haemostatic abnormality equivalent to mild thrombophilia
European guidelines recommend considering ABO blood group when counselling women about hormonal contraceptive choice alongside other thrombophilic risk factors. Progestin-only contraceptive options carry substantially lower VTE risk and are worth discussing with a clinician.

Prolonged immobilisation — long-haul flights (>4 hours), post-surgical bed rest, cast immobilisation — represents the most actionable modifiable exposure. In people with non-O blood type, compression stockings reduce travel-related asymptomatic DVT by up to 18-fold in high-risk individuals¹¹¹¹ compression stockings reduce travel-related asymptomatic DVT by up to 18-fold in high-risk individuals
Randomised data from the LONFLIT studies; NNT 37 for high-risk travellers and should be used consistently on flights over 4 hours.

Monitoring VWF antigen and activity levels can help quantify the individual haemostatic burden, particularly before elective surgery or procedures, and gives clinicians a baseline against which to assess change over time.

Interactions

The interaction with Factor V Leiden (rs6025 in the F5 gene) is the most clinically significant gene-gene interaction documented in thrombosis genetics. Carrying both non-O blood type and Factor V Leiden multiplies VTE risk to roughly 23-fold above baseline — far greater than either factor alone (1.7x and 4.6x respectively). Similarly, combination with the prothrombin G20210A variant (rs1799963) amplifies risk substantially above either variant alone.

The ABO locus is also associated with elevated circulating levels of soluble P-selectin and E-selectin, two adhesion molecules that also rise with inflammatory states. Individuals carrying rs1800629 (TNF-alpha promoter variant) or rs1205 (CRP) in addition to non-O blood type may have compounded pro-inflammatory and pro-thrombotic physiology, though combined GWAS evidence for specific compound effects remains preliminary.