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Genetics and Genomics of Chronic Inflammatory Disorders, I: Inflammatory Bowel Disease 

Genetics and Genomics of Chronic Inflammatory Disorders, I: Inflammatory Bowel Disease
Chapter:
Genetics and Genomics of Chronic Inflammatory Disorders, I: Inflammatory Bowel Disease
Author(s):

Saad Pathan

and Derek P. Jewell

DOI:
10.1093/med/9780199896028.003.0028
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date: 30 October 2020

Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory diseases of the intestine that can begin at any age, even in children. Both diseases are commonly known as inflammatory bowel diseases (IBD). They represent a major challenge, because their causation is unclear, medical treatment is far from satisfactory, and many patients require major surgery. The turning point in the genomic portrait of IBD was facilitated with the high-resolution detection of loci that individually have a very modest influence. There is compelling evidence for over 163 distinct genetic loci, and this has to date been unprecedented for a complex disease. More specifically, there are at least 30 distinct loci that are associated with the phenotype of CD, and 23 loci with UC. Moreover, the boundaries between CD and UC are blurred by the 110 loci that are exquisitely shared. There are also remarkable parallels and paradoxes between other diseases, such as inflammatory, autoimmune, infectious and primary immunodeficiencies. The evidence implies that an unbalanced triggering of the mucosal immune system towards commensal intestinal flora results in the development of chronic inflammatory diseases. The selection pressures for the common IBD associated variants are most likely to have been protection from infectious diseases. The disease associated variants within the genes, such as NOD2, IL23R, ATG16L1 and CARD9 have the potential to adversely affect innate and adaptive immunity, as well as mucosal barrier integrity and autophagy. A variety of causative variants have also been discovered within the associated loci that could render individuals susceptible to IBD and might influence the behaviour of the phenotype. The association between the exceedingly rare homozygous mutations and unusual phenotypes adds an additional dimension to probe the biology, as exemplified by the interleukin IL-10 receptor and IL-10 cytokine deficiencies. The new insights from unravelling the multitude of disease mechanisms are a prerequisite for novel personalised therapeutic strategies.

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