Cindy Boer

142 | Chapter 3.2 As, individuals can be both carriers of MGP risk alleles and VKROC1 haplotypes, we examined the combined effects of the VKORC1 -BB haplotype and MGP -risk allele carriers (T/*). We stratified our study population into VKORC1 BB-haplotype or AA/AB carriers, which was then further stratified into carriers (T/*) and non-carriers (A/A) of the MGP risk allele, rs1800801 ( Figure 1 and Supplementary Table 3 ). Acenocou- marol users whom either were carriers of the MGP risk alleles (T/*) or carriers of the VKORC1 BB-haplotype has a significant increased risk of osteoarthritis incidence and progression. Individuals whomwere carriers of both the VKORC1 BB-haplotype and the MGP risk allele had a fourfold increased risk of osteoarthritis incidence and progres- sion (OR=4.18, 95%CI=2.69-6.50, Figure 1 ). Interestingly, VKORC1 AA/AB-haplotype carriers who were not carriers of the MGP- risk allele (A/A) did not have a significant in- creased risk of overall OA progression/incidence when using acenocoumarol (OR=1.72, 95%CI=0.93-3.19, Figure 1 ). Discussion We demonstrated that use of the acenocoumarol was associated with a higher risk of overall OA incidence/progression in than non-users. We observed that the increased OA risk in acenocoumarol users varied based on genetic variants affecting the vitamin K cycle with VKA use. Acenocoumarol users with the MGP risk allele and VKORC1 BB-hap- lotype, had a fourfold higher risk for overall OA incidence/progression. The VKORC1 BB-haplotype is associated with a higher expression of VKORC1 , associated with greater vitamin K activity; however, individuals who are VKORC1 BB- haplotype carriers also require and receive higher dosages of VKA for the desired an- ticoagulation effect[23]. Intuitively, the anticoagulation, amount of VKORC1 inhibition, should be similar in all users regardless of VKORC1 haplotype since the amount of an- ticoagulation is the dosing measurement, not VKORC1 expression. However, vitamin K availability levels differ significantly between tissues[25, 26] and warfarin affects vita- min K inhibition differently in liver compared to bone[27-29]. In liver, another enzyme in addition to VKORC1 , is available for the recycling of vitamin K into its active form, NQO1(NAD(P)H quinone oxidoreductase 1). This enzyme is not present in bone tissue, causing bone tissue to be more susceptible to VKA dosages than liver tissue[28-30]. Thus, higher VKA dosages in VKORC1 BB-haplotype carriers needed for desired inhibi- tion of vitamin K-dependent blood coagulation proteins in the liver might be too high of a dosage for VKORC1 functioning in the joint.