Cindy Boer

270 | Chapter 6 using age of osteoarthritis onset as phenotype rather than osteoarthritis status. Other examples of (environmental) risk factor incorporation into osteoarthritis phenotypes might be to examine disease progression over time, changes of osteoarthritis risk with changes in environmental risk factors, such as diet (gut microbiome) and drug use, over time. Acknowledging osteoarthritis as a syndrome will emphasize phenotype defini- tion as the key importance in osteoarthritis research. Accurate identification of osteo- arthritis phenotypes, will increase GWAS power by reducing heterogeneity. Follow-up research can then link underlying mechanisms to the specific phenotypes, possibly leading to the identification of specific clinical subsets of osteoarthritis patients. Possi- bly improving patient care by providing the possibility of future targeted/personalized therapeutic interventions based on the clinical subset of osteoarthritis. Thus by re-de- fining osteoarthritis as a syndrome, we can improve osteoarthritis research, improve patient care by possibly future development of targeted treatments. Microbiomics: It’s all in the gut The human microbiome, specifically the human gastrointestinal microbiome, has been shown to play an important role in health and disease[43, 44], possibly including oste- oarthritis ( Chapter 5 ). Although, the microbiome is an easy and attractive therapeutic target for osteoarthritis, no conclusive evidence of causality is established. Partially, this can be attributed to the novelty of large scale microbiomics data: the limited availability of data, lack of standardization in data processing, methodology and analysis. Moreover, much is unknown on the exact molecular mechanisms or pathways by which the human microbiome functions in health and disease. This also means that for most microbiome and disease associations causality is not known. However, for future research it is abso- lutely essential that the causality and the directionality (does Streptococcus spp. cause pain or does pain lead to Streptococcus spp. colonialization) is established. There are several possible research methods by which causality of Streptococcus spp. on osteoarthritis could be investigated. These would include longitudinal analysis of gastrointestinal composition and osteoarthritis related pain, in order to examine if an increase in Streptococcus spp. is followed by an increase in joint inflammation and pain. The detection of Streptococcus (or bacterial) metabolites and excreted membrane vesicles in the blood and joint tissue (e.g. synovium) and if these can trigger joint in- flammation and/or pain, would also be evidence of a causal relationship. In addition, to establishing causality, identifying the exact species or strain of Streptococcus bacteria is of therapeutic importance. If the association is causal and decrease of streptococcus spp.