Cindy Boer

266 | Chapter 6 Novel risk factors for osteoarthritis: the Microbiome As a complex disease, osteoarthritis risk is determined by a combination of genetic and environmental risk factors. Each of these risk factors, however does not exist alone in a vacuum, all are interconnected, forming complex layers of interactions ( Figure 5 ). A “novel” layer in this complex system is the microbiome. C hapter 5 investigated the gastrointestinal microbiome composition as a possible risk factor for osteoarthritis. Changes in composition and function of the gastrointestinal microbiome are affected by a large number of host and environmental factors and have been associated with many common diseases and health deficits[43, 44]. Osteoarthritis is no exception to this, and in Chapter 5.1 increased abundance of Streptococcus spp. in the gastrointestinal mi- crobiome was associated with increased inflammation and osteoarthritis related pain and inflammation in the knee joint. If the association is causal, it would be a significant finding for possible therapeutic intervention, as pain is the main disabling symptom in osteoarthritis[45]. Both for symptomatic relief, as pain elevation, as well as long-term disease modification (reduced inflammation damage). Some preliminary studies have shown that antibiotic use could reduce chronic low back pain, postulated to be caused by a low grade inflammation caused by the gastrointestinal microbiome[46, 47]. Other possible methods exist and/or are under development to alter the composition of the gastrointestinal microbiome (faecal transplant and probiotics, diet intervention) and thus may also be investigated as therapeutic strategies for osteoarthritis. What does the future hold for osteoarthritis? It has been more than a decade ago that the first osteoarthritis GWAS was performed and since this first effort our knowledge of osteoarthritis genetics has significantly ex- panded, as has been presented in this thesis. Despite the increase in associated genetic loci, pathways and risk factors, much remains unknown on osteoarthritis pathology. The following recommendations can be implemented to aid the elucidation of the ge- netic architecture of osteoarthritis and disease pathology: (i) expansion of osteoarthri- tis GWASs, (ii) Re-defining osteoarthritis , (iii) Microbiomics: It’s all in the gut and (vi) Post GWAS era: move to the clinic . All four are interconnected, and will be needed to bring preventive or curative treatments closer for one of the world’s oldest diseases Expansion of osteoarthritis GWAS: method, size, population, and phenotype In the last few years we have seen an effective sevenfold increase of reported osteoar- thritis associated loci, predominantly driven by large scale osteoarthritis GWAS. For