Autoimmune diseases are on the rise globally, and the largest increase is observed in highly developed countries. They contribute significantly to morbidity and mortality, posing a substantial burden on health care systems worldwide. Tumor necrosis factor-alpha (TNF) is a central pro-inflammatory cytokine whose upregulation plays an important role in the pathogenesis of many autoimmune diseases. TNF inhibitors (TNFi) are therefore widely used for a range of autoimmune conditions such as rheumatoid arthritis and Crohn's disease. However, response to treatment is variable among patients and up to 40% of patients do not improve with TNF inhibitor therapy. There are very few pharmacogenomics genome-wide association studies that could delineate clear links between genetic variants and treatment outcome, and these studies are especially lacking in Arab populations. The team will establish a genetic correlation with response to treatment by recruiting patients with inflammatory arthritis and inflammatory bowel diseases and performing exome-wide association studies for the efficacy of TNF inhibitors. Furthermore, the team will assess the prevalence of both newly identified response-associated variants and those found in TNFi-response candidate genes in genomes sequenced by the Qatar Genome Programme, to understand the extent of their impact in the local population. Additionally, since autoimmune diseases are thought to be greatly influenced by the environment, the team hypothesizes that some of the variability is mediated by epigenetic factors, and they will perform an epigenome-wide association study to investigate the effect of differential DNA methylation on TNF inhibitor-response. Finally, they will validate the effect of variants on the functioning of the TNF signaling cascade in humanized C. elegans.