Abstract
Background:The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8×10–7), which was included in the genome-wide significant KAT8 locus.Objective:Our study aimed to investigate whether the relationship between rs9923231 and dementia persists only for certain dementia sub-types, and if those taking warfarin are at greater risk.Methods:We used logistic regression and data from 238,195 participants from UK Biobank to examine the relationship between VKORC1, risk of dementia, and the interplay with warfarin use.Results:Parental history of dementia, APOE variant, atrial fibrillation, diabetes, hypertension, and hypercholesterolemia all had strong associations with vascular dementia (p < 4.6×10–6). The T-allele in rs9923231 was linked to a lower warfarin dose (βperT - allele = –0.29, p < 2×10–16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. However, the risk of vascular dementia was not affected by warfarin use in carriers of the T-allele.Conclusion:Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia.
Highlights
Warfarin is the most prescribed anticoagulant worldwide [1] and is commonly used as a treatment for atrial fibrillation (AF) [2]
We explored the relationship between suspected dementia, atrial fibrillation, warfarin use, and rs9923231, whose T-allele is associated with a reduction in the dose of warfarin [3, 7, 8]
We found a significant association between rs9923231 and suspected vascular dementia (VaD), but not between rs9923231 and either suspected general dementia or suspected Alzheimer’s dementia (ADem)
Summary
Warfarin is the most prescribed anticoagulant worldwide [1] and is commonly used as a treatment for atrial fibrillation (AF) [2]. J. Mur et al / Variation in VKORC1 Is Associated with Vascular Dementia (VKOR), effectively interfering with the vitamin K cycle required for coagulation of blood [3]. The genetic variant rs9923231 (VKORC1) is associated with differences in the coagulation of blood and consequentially with sensitivity to the drug warfarin. Variation in VKORC1 has been linked in a gene-based test to dementia/Alzheimer’s disease in the parents of participants, with suggestive evidence for an association for rs9923231 (p = 1.8 × 10–7), which was included in the genome-wide significant KAT8 locus. The T-allele in rs9923231 was linked to a lower warfarin dose (perT-allele = –0.29, p < 2 × 10–16) and risk of vascular dementia (OR = 1.17, p = 0.010), but not other dementia sub-types. Conclusion: Our study reports for the first time an association between rs9923231 and vascular dementia, but further research is warranted to explore potential mechanisms and specify the relationship between rs9923231 and features of vascular dementia
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