Cindy Boer

General Introduction | 23 1.1 Other than using endophenotypes, stratified osteoarthritis phenotypes can also be used to reduce heterogeneity and increase GWAS power. Stratified phenotypes aim to differentiate subgroups within the diagnosis of osteoarthritis[25]. These can be based on a single pathological phenotype of osteoarthritis (e.g., amount of osteophytes or bone marrow lesions present) or based on multiple characteristics (clinical, radio- graphic osteoarthritis, joint function and disability)( Figure 6 ). Indeed, multiple broad term categories could be recognized for osteoarthritis stratified phenotypes based on either structural (pathological structure formations) aetiological (based on the under- lying cause of osteoarthritis) characteristics or pain (clinical osteoarthritis, presence of inflammation), joint function/disability (range of motion, gait), and molecular (which pathological molecular pathway is dominant) ( Figure 6 ). Many more stratified osteo- arthritis phenotypes might be possible and will be discovered as continued work on os- teoarthritis and its phenotypes yields more genetic loci and etiological insight into the biological mechanism underlying this disease. Chapter 2.2 and 3.1 will demonstrate the results of using structural osteoarthritis phenotypes for the identification of genetic variants associated with hand osteoarthritis. Osteoarthritis pain, inflammation & the microbiome As described, the -itis suffix in osteoarthritis comes from the Ancient Greek ῖ τις (îtis) meaning “pertaining to”. However, in recent years the –itis suffix in a disease name has come to be associated with inflammation. In recent history there has been much de- bate, as osteoarthritis was thought to be a disease without any inflammatory involve- ment[52, 53]. Currently, however, the involvement of synovial inflammation in osteoar- thritis pathology has been well established, and thought to be one of the causes for the pain seen in osteoarthritis affected joints[54]. Several causes for this inflammation have been postulated, such as traumatic joint injury (sports, accidents, falls etc.), leading to joint damage and inflammation, triggering more damage and inflammation. A novel fac- tor postulated to be involved in osteoarthritis related inflammation is the gastrointesti- nal(gut) microbiome[55, 56] ( Figure 6 ). The gastrointestinal microbiome consists of trillions of microorganisms, mainly bacteria, living in our intestinal tract. These microorganisms are important in the di- gestion of our food, and recent research has shown that there is also a very important role for the microbiome in health and disease. This has become clear by observing the composition of the microbiome, or rather the change in composition of the microbiome (dysbiosis) which has been linked to several disorders and diseases [57, 58]. Most nota- bly the effect of the microbiome on obesity and the effect of obesity on the microbiome