Cindy Boer

280 | Chapter 7 two novel thumb osteoarthritis loci were identified. One of the thumb osteoarthritis severity osteoarthritis loci (rs10916199) was also associated with clinical thumb os- teoarthritis. Using multiple approaches that leverage different levels of information and functional data, the underlying biological mechanism and candidate gene for this lo- cus (rs10916199) was investigated. WNT9A was identified as possible novel gene involved in osteoarthritis pathogenesis, with rs1158850 as potential causal variant in this locus. In addition, several previously identified genetic loci for osteoarthritis were shown to also confer risk for osteoarthritis across multiple joints: TGFα, RUNX2, CO- L27A1. ASTN2. IL11 and the GDF5 -loci. Chapter 3 continued the use of this hand osteoarthritis severity phenotype to identify the second hand osteoarthritis associated loci. Again, using follow-up translational re- search a novel osteoarthritis associated gene was discovered. However, in the second part of this chapter, the implications of this novel osteoarthritis gene association are put to the test and revealed some serious clinical implications. Demonstrating the im- portance of in depth follow-up research and value of genetic studies for osteoarthritis research. In Chapter 3.1 an osteoarthritis phenotype, which quantified the severity of ra- diographic osteoarthritis, was used to identify the second genetic loci associated with hand osteoarthritis. A coding variant in the MGP gene was associated with increased risk of hand osteoarthritis. This variant showed allele specific gene expression in car- tilage tissue, the risk variant significantly reduced MGP gene expression. MGP is an es- sential inhibitor of cartilage calcification, thus reduced MGP expression could lead to increase cartilage calcification and higher risk of osteoarthritis. In addition, MGP can only inhibit cartilage calcification if γ-carbolized by vitamin K. Demonstrating the link between low vitamin K status and high risk of osteoarthritis. Using this new knowledge, Chapter 3.2 investigated the possible role of vitamin K antagonist anticoagulants in osteoarthritis risk and progression. Vitamin K mediated γ-carboxylation is also essential for several blood coagulation factors, thus most an- ticoagulant medication inhibits this process. The vitamin K antagonist anticoagulants inhibit the function of VKORC1 , an essential protein in the Vitamin K mediated γ-car- boxylation pathway. Individuals taking the vitamin K antagonist anticoagulant aceno- coumarol, were found to have a twofold greater risk of incidence and progression of knee and/or hip osteoarthritis then those not using acenocoumarol. Next, individuals whom were carrier of the MGP osteoarthritis risk allele and the VKORC1 B- haplotype, associated with a higher dose of acenocoumarol, had a more than