rs8176746
badMag 5.5This is a protein-altering variant in the ABO gene.
Key Literature Trait Associations
Venous thromboembolism
Non-O ABO blood groups, including blood group B (tagged by the T allele of rs8176746), are the most common inherited genetic risk factor for venous thromboembolism (VTE). A meta-analysis of 38 studies (n=10,305 VTE cases) found a pooled OR of 2.09 (95% CI 1.83–2.38) for non-O versus O blood groups; the BB genotype specifically showed OR ~1.87–2.44. The mechanism involves ABO-mediated regulation of von Willebrand factor and factor VIII levels, with non-O individuals having ~25% higher circulating VWF. Effects are consistent across ancestry groups.
Cerebral venous thrombosis
Blood groups A, B, and AB (all carrying at least one non-O allele, including the B allele tagged by rs8176746 T) confer substantially elevated risk of cerebral venous thrombosis (CVT). A GWAS with replication (882 cases, 1,205 controls) identified the ABO locus as the first genome-wide significant susceptibility locus for CVT, with non-O blood groups showing 2.85-fold increased risk compared to blood group O (95% CI 2.32–3.52, p=2.00×10⁻¹⁶). This likely reflects higher VWF and factor VIII levels mediated by non-O ABO glycosyltransferase activity.
ABO Blood Group B Antigen
The Leu265Met substitution encoded by rs8176746 is one of seven canonical amino-acid differences that switch the ABO glycosyltransferase from A-specificity (adding N-acetylgalactosamine) to B-specificity (adding galactose). Individuals carrying the T allele at this position produce the B antigen on red cell surfaces. Like blood type A, blood type B is associated with elevated von Willebrand factor and Factor VIII levels relative to blood type O, contributing to a modestly higher thrombosis risk.
Von Willebrand factor levels
The ABO locus, including rs8176746, is one of the strongest genetic determinants of circulating von Willebrand factor (VWF) antigen levels. GWAS and linkage analyses identify ABO signals at p<7.9×10⁻¹³⁹ for VWF levels; the ABO locus explains approximately 24.5% of VWF level variance. Non-O blood groups including B (T allele) are associated with higher VWF levels, while a small candidate-gene study in VWD type 1 patients found rs8176746 associated with reduced VWF antigen in that specific clinical context. The VWF-elevating effect of non-O alleles underlies the ABO blood group's well-established associations with thrombosis.
Myocardial infarction
Non-O ABO blood groups (including group B, tagged by the T allele of rs8176746) are associated with increased myocardial infarction (MI) and ischemic stroke risk. A systematic review and meta-analysis of 28 studies found non-O blood groups associated with MI (OR 1.28, 95% CI 1.17–1.40) and ischemic stroke (OR 1.17, 95% CI 1.01–1.35). The mechanism likely involves elevated VWF and factor VIII levels mediated by non-O ABO antigens on platelet and endothelial surfaces, promoting thrombotic plaque formation.
Pancreatic cancer
Non-O ABO blood groups, including blood group B (tagged by rs8176746 T allele), are consistently associated with increased pancreatic ductal adenocarcinoma (PDAC) risk across multiple populations. A large case-control consortium (8,027 cases, 11,362 controls) found non-O groups at OR 1.28 (95% CI 1.15–1.42) among secretors; a Japanese case-control study found BB genotype at OR 3.28 (95% CI 1.38–7.80). Meta-analyses confirm blood group A carries the strongest individual risk, but group B also confers elevated risk compared to O. The mechanism may involve ABO antigens on pancreatic ductal epithelium modulating immune surveillance.
Angiopoietin-2 levels
A GWAS for circulating endothelial growth factors identified rs8176746 in the ABO gene as a genome-wide significant locus for plasma angiopoietin-2 (Ang-2) levels (p=2.07×10⁻⁸ in the Framingham Heart Study, n=3,571; replicated at p=0.001 in SHIP, n=3,184). Angiopoietin-2 is stored in Weibel–Palade bodies of vascular endothelium alongside VWF, and ABO glycosylation of endothelial surface antigens likely modulates Ang-2 secretion. Elevated Ang-2 is associated with vascular inflammation and endothelial dysfunction.
▶GWAS Catalog Trait Associations (25)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (25)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
▶Research that mentions this SNP (4)
▶Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization studyMeta-analysisN=60,139Sara Lindström et al.(2017)· Human Genetics
Mendelian Randomization study examining the causal relationship between obesity (BMI) and venous thromboembolism using 95 BMI-associated SNPs in 7,507 VTE cases and 52,632 European ancestry controls. FTO rs1558902 showed the strongest individual association with VTE (OR 1.07, P = 0.005), and genetically predicted high BMI was significantly associated with increased VTE risk (OR 1.59 per SD increase in BMI, P = 5.8 × 10^-6), providing evidence for a causal relationship between obesity and VTE.
▶Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis BAssociationN=6,033Jiang DK et al.(2015)· Hepatology
A genome-wide association study of 83 plasma proteins relevant to cardiovascular disease in 3,394 European subjects identified 79 genome-wide significant loci (p<5e-8), with 55 replicating in independent cohorts (n=2,639). Using eQTL analysis and network methods, the authors proposed plausible causal mechanisms for 25 trans-acting loci including post-translational regulation of KITLG by MMP9 and several receptor-ligand pairs. Multiple loci showed evidence of causal association with coronary artery disease risk.
▶The dual and opposite role of the TM6SF2‐rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: A meta‐analysisAssociationN=13,577Carlos J. Pirola et al.(2015)· Hepatology
This doctoral thesis comprises three studies on metabolic syndrome-related traits. Study III is a GWAS identifying seven novel loci associating with circulating inflammatory markers (cytokines and adhesion molecules) in 5,284 Finnish individuals from NFBC1966, with meta-analysis including three additional Finnish populations totaling 13,577 participants. Studies I and II use Mendelian randomization and association analysis to examine metabolic effects of lipid-lowering therapies and NAFLD risk alleles (PNPLA3 rs738409-G, TM6SF2 rs58542926-T, GCKR rs780094-T/rs1260326-T, LYPLAL1 rs12137855-C, and NCAN rs2228603-T).
▶A Genome‐Wide Association Study for Serum Bilirubin Levels and Gene‐Environment Interaction in a Chinese PopulationAssociationN=3,294Xiayun Dai et al.(2013)· Genetic Epidemiology
GWAS study of 3,294 European ancestry individuals from the eMERGE Network examining serum bilirubin and other liver function tests. Strong association signal at UGT1A1 locus (rs887829, beta=0.15, p=1.30×10^-118) confirmed in both adult and pediatric populations. Additional associations identified in SLCO1B1, SLCO1B3, TDRP, ZMYND8, and ABO locus. Phenome-wide analysis revealed protective effect of TA7 repeat against cerebrovascular disease (OR=0.75, p=0.0008).
Gene information from NCBI Gene. Variant classifications from ClinVar.
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