Cindy Boer

134 | Chapter 3.2 Abstract Objectives: Vitamin K is hypothesized to play a role in osteoarthritis pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, Matrix Gla Protein (MGP), is as- sociated with an increased risk for osteoarthritis. Vitamin K antagonists anticoagulants (VKA), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKA likely also affect the functioning of other vitamin K-dependent proteins such as MGP. Methods : We investigated the effect of acenocoumarol usage on progression and inci- dence of radiographic osteoarthritis in 4,492 participants of the Rotterdam Study co- hort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association. Results : Acenocoumarol usage was associated with an increased risk of osteoarthri- tis incidence and progression (OR=2.50, 95%CI=1.94-3.20), both for knee (OR=2.34, 95%CI=1.67-3.22) and hip osteoarthritis (OR=2.74, 95%CI=1.82-4.11). Among aceno- coumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP osteoarthritis risk allele (rs1800801-T) had an increased risk of osteoarthritis incidence and progression (OR=4.18, 95%CI=2.69-6.50), while this relationship was not present in non-users of that group (OR=1.01, 95%CI=0.78-1.33). Conclusions: These findings support the importance of vitamin K and vitamin K-de- pendent proteins, as MGP, in the pathogenesis of osteoarthritis. Additionally, these re- sults may have direct implications for the clinical prevention of osteoarthritis, support- ing the consideration of direct oral anticoagulants in favour of VKAs.