Cindy Boer

General Discussion | 265 6 ◄ Figure 4: The biological role of MGP and Vitamin K. A graphical summary of the functions of MGP, vitamin K in calcification, the effect underlying genetic variation and Vitamin K antagonist anticoagulant (VKA) use. InactiveMGP or uncarboxylizedMGP, is γ –carboxylized by vitamin K into active of carboxylized MGP (cMGP), which is transported to the extracellular matrix to bin Ca 2+ , to prevent the formation of calcium crystals. Variants in MGP result is less expression of MGP and are associated with higher risk of osteoarthritis. VKORC1 B haplotype causes increased expression of VKORC1, compared to VKORC1 A-haplotype. VKORC1 B-haplotype associated with hight maintenance dosages of VKAs, conversely VKOC1 A-haplotype is associated with decreases VKA dosages. VKAs inhibit VKORC1 function, and thereby also γ –carboxylation of MGP, increasing osteoarthritis risk. elderly[37], a group already at higher risk of osteoarthritis, and VKA users are advised to limited their dietary vitamin K intake, resulting in additional risk for low vitamin K status and therefore, possibly osteoarthritis. Interestingly, the MGP risk variant poses a large risk for osteoarthritis with environmental interaction (VKA use), while in the GWAS, the effect size was small ( Chapter 4 ). This Indicates that GWAS effect size does not predict the clinical or therapeutic impact of the associated SNV[2]. It also underlines the necessity to understand the bio- logical mechanism behind the genetic association, in order to fully recognize its clinical impact. In addition, although first only found to be associated with hand and finger os- teoarthritis and later nominal significant with knee osteoarthritis ( Chapter 4 ), the MGP risk variants pose risk for hip and knee osteoarthritis in VKA users. Indicating non joint specific role for MGP and vitamin K in osteoarthritis, further increasing the therapeutic potential importance of the vitamin K-cycle. Osteoarthritis clinical implications of MGP These genome-wide hand osteoarthritis associated variants in MGP have illustrated the a possible novel pathway associated with osteoarthritis, i.e., chondrocalcinosis. In addition, they have elucidated underlying fundamental biological mechanisms and confirmed prior epidemiological observations on vitamin K and osteoarthritis[34, 35, 38, 39]. More importantly, these variants and subsequent follow-up characterization of these variants have identified vitamin K as possible target for pharmacotherapy and pharmacogenetic clinical trials. This was the result of only a single osteoarthritis associ- ated locus and only a handful of other osteoarthritis loci have been deeply translational investigated[11, 40-42]. Tus the potential impact of deep translation research on those many remaining variants, for example the 52 novel reported in the GO-consortium, could be significant on osteoarthritis understanding and therapeutic research.