Cindy Boer

General Discussion | 263 6 on properties or pathological features of these tissues. Although interpretation of GWAS findings is time consuming, laborious, and requires additional experimental validation, it is essential if we want to use GWAS to learn more about osteoarthritis aetiology and eventually identify novel therapeutic targets. From osteoarthritis GWAS to Clinic For drug development, treatments based on human genetic evidence of disease associa- tion are twice as likely to become approved[31]. When for a GWAS association the caus- al gene is clearly defined, the approval for drug development increases to four-fold[32]. Therefore, the steps given in the previous paragraph are absolutely essential if we wish to advance our understanding of osteoarthritis pathology and hope to translate this into knowledge or treatments beneficial for patients. Chapter 3 , represents the path from GWAS finding to identification of a causal gene and pathways, to clinical implication and possible therapeutic intervention. MGP, Vitamin K, anticoagulants and Osteoarthritis Using a summarized quantitative osteoarthritis phenotype, SNVs in the Matrix Gla-Pro- tein ( MGP ) gene were genome-wide associated with hand KLsum ( Chapter 3.1 ). Trans- lational research indicated MGP as the causal gene, where the GWAS associated SNVs reduce MGP expression in cartilage and bone. MGP , is an essential inhibitor of calcifi- cation in soft tissues such as the cartilage, it binds to Ca 2+ preventing the formation of calcium crystals (basic calcium phosphate crystals)[33] ( Figure 4 ). MGP is dependent on γ -carboxylation by vitamin K for its function, validating low vitamin K level as risk factors of osteoarthritis[34-36]. Linking a modifiable risk factor, vitamin K levels, with a genetic risk factor for osteoarthritis. In Chapter 3.2 , the interaction between vitamin K and MGP risk variants was investigated. Vitamin K antagonists anticoagulants (VKAs) inhibit the functioning of the VKORC1 protein in the vitamin K cycle, thereby inhibi- tion the γ –carboxylation and thus functioning of MGP ( Figure 4 ). There was a two- fold increased risk for osteoarthritis incidence and progression in VKA users, compared to non-users. When the underlying genetics were taken into account, MGP risk allele carrier and VKORC1 B -haplotype carrier, VKA users had a three-fold increased risk of osteoarthritis progression ( Chapter 3.2 ). MGP, VKORC1 genetics and Osteoarthritis In the populations of European ancestry, 48% are carriers of the MGP risk allele and the VKORC1 B -haplotype, exposing half of the VKA users to very high risk of osteoarthritis incidence and progression. Additionally, VKAs are most commonly prescribed to the