Epidemiology and Pathogenesis of Ulcerative Colitis

Inflammatory bowel disease is a global disease in the 21st century. We aimed to assess the changing incidence and prevalence of inflammatory bowel disease around the world.

Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.

Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations 1 . Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC 2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy 4 , in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.