rs9923231
badMag 7.5This is a regulatory region variant variant in the VKORC1 gene.
Key Literature Trait Associations
Warfarin Sensitivity
The strongest genetic predictor of warfarin dose. The T allele reduces VKORC1 expression by ~44%, meaning less warfarin is needed to inhibit vitamin K recycling. Explains ~25% of warfarin dose variability. Combined with CYP2C9 genotyping, enables personalized dosing.
Vascular dementia
A large UK Biobank analysis (n=238,195) found that the T allele of rs9923231 was associated with increased vascular dementia risk (OR=1.17, p=0.010). The association was specific to vascular dementia and was not observed for other dementia subtypes. Warfarin use did not modify the association, suggesting a mechanism independent of anticoagulation, possibly involving vitamin K's role in nervous system Gla-protein carboxylation. This finding requires replication given the modest effect size and single-study provenance.
Cardiovascular disease
The G allele (reference allele, associated with higher VKORC1 expression) was associated with higher risk of cardiovascular and cerebrovascular diseases in a meta-analysis of 10 case-control studies. The A (T) allele carriers showed an OR of 0.74 for developing cardiovascular/cerebrovascular disease versus GG homozygotes (dominant model OR=0.67, p<0.001). The mechanism may involve differential vitamin K-dependent coagulation factor activity or vascular calcification inhibition. Findings require replication in independent prospective cohorts.
Osteoporosis
A 2026 systematic review and meta-analysis of 6 studies (n=7,335) found that VKORC1 risk alleles, including rs9923231, were modestly associated with osteopenia and osteoporosis (pooled OR=1.16, 95% CI 1.01–1.35, p=0.041), with negligible heterogeneity across studies (I²=0%). The biological basis likely involves VKORC1's role in vitamin K-dependent carboxylation of osteocalcin, a bone matrix protein essential for mineralization. The authors noted the modest effect size and called for additional research to establish clinical relevance.
▶GWAS Catalog Trait Associations (2)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (2)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
See cases; Thrombus; VKORC1-related disorder; Venous thromboembolism; Warfarin response; acenocoumarol response - Dosage; not specified; phenprocoumon response - Dosage; phenprocoumon response - Toxicity; warfarin response - Dosage; warfarin response - Efficacy; warfarin response - Toxicity
View on ClinVar →▶Research that mentions this SNP (3)
▶Brief Report: Single‐nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in AsiansAssociationN=3,739Rachel Kaiser et al.(2013)· Arthritis & Rheumatism
Two SNPs in VKORC1 (rs9934438 and rs9923231) were identified as genetic risk factors for systemic lupus erythematosus (SLE) in Asian populations. In discovery cohort (263 SLE cases, 357 controls), both SNPs showed strong associations (OR=2.40-2.45, p=6.1×10^-9 to 2.4×10^-9), which were confirmed in a larger replication cohort (1496 cases, 993 controls) with OR=1.53-1.54 (p=4.3-5.1×10^-6), and remained significant after ancestry adjustment (OR=1.34, p=0.0029-0.0032).
▶VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest ChinaAssociationN=260Qiang Gu et al.(2010)· European Journal of Clinical Pharmacology
Study of 127 southwest Chinese Han patients with mechanical heart valve prostheses examined genetic polymorphisms in VKORC1 -1639G>A (rs9923231), CYP2C9 (*3: rs1057910, IVS3-65G>C: rs9332127), and EPHX1 691A>G (rs4653436) as predictors of warfarin maintenance dosage. A multiple linear regression model incorporating these genetic variants plus age and body weight explained 74.3% of interindividual variability in warfarin dosing, with VKORC1 -1639G>A being the strongest predictor (r=0.769, p<0.001).
▶Association of warfarin dose with genes involved in its action and metabolismAssociationN=201Mia Wadelius et al.(2007)· Human Genetics
An association study of 201 warfarin-treated patients found that polymorphisms in VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, and APOE were significantly associated with warfarin dose requirement (P < 0.000175 for VKORC1 and CYP2C9). A multiple regression model incorporating VKORC1, CYP2C9, PROC, and non-genetic factors (age, bodyweight, drug interactions, treatment indication) accounted for 62% of the variance in warfarin dose.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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