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Embed code for: Genetic Studies of Inflammatory Bowel Diseases
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Genetic Studies of Inflammatory Bowel Disease
Enache Mihaela Ioana
What causes IBD?
IBD is the result of an innapropriate inflammatory response that results in chronic intestinal damage and life-threatening complications
There are two main phenotypes- Crohn's Disease (CD) and Ulcerative Colitis (UC), both with different histopathological features and clinical manifestation
Prevalence: 250-300 per 100 000 individuals (CD)
50-100 per 100 000 individuals (UC)
The most accepted theory regarding susceptibility is a multifactorial model in which polygenic inheritance at hundreds of genetic loci, each with small effects, add up along with non-genetic factors such as diet, environment, smoking habits, breastfeeding, microbiome composition and immune response
Genetic research evolved from family and population-based studies, to linkage analysis, to genome-wide association studies (GWAS). Next generation sequencing represents the next level, especially exome targeted sequencing
First susceptibility gene for CD -> NOD2 (role in autophagy)
Other autophagy-related genes -> IRGM and ATG16L1
Association with auto-immune diseases -> GWAS defined the genetic
overlap between CD and other immune-related diseases
Up to this date -> over 200 susceptibility loci for IBD and ~300 potential candidate genes
Overall, the percentage of the expected heritability is small (20-25%)
Individual and family-based analysis for clinical use
Research tool to complement GWAS
Risk prediction for IBD
From Frontiers in Immunology
Early-onset IBD and Very-Early-Onset IBD
Rare and severe disease presentations
Cause: monogenic defects-> rare, single genetic mutations
IL-10 or IL-10R, NCF2, XIAP, LRBA
CD or CD-like (increasing genetic burden)
Exome sequencing was successfully used in the case of a 15 months old male patient with intractable IBD
He had a mutation on the XIAP gene
A similar case involved a 5-mo-old female patient with colonic IBD
Exome sequencing revealed a mutation on the MEFV gene, resulting in a diagnosis of familial Mediterranean fever
Inflammatory Bowel Disease is one of the most genetically complex conditions
In each case the patient has an individual genetic profile
NGS is an efficient tool in disease etiology, diagnosis and treatment
Liu, Jimmy Z., and Carl A. Anderson. “Genetic Studies of Crohn’s Disease: Past, Present and Future.” Best Practice & Research. Clinical Gastroenterology 28.3 (2014): 373–386. PMC. Web. 6 Nov. 2016.
Cardinale, Christopher J et al. “Impact of Exome Sequencing in Inflammatory Bowel Disease.” World Journal of Gastroenterology : WJG 19.40 (2013): 6721–6729. PMC. Web. 6 Nov. 2016.
McGovern, Dermot, Subra Kugathasan, and Judy H. Cho. “Genetics of Inflammatory Bowel Diseases.” Gastroenterology 149.5 (2015): 1163–1176.e2. PMC. Web. 6 Nov. 2016.
Cleynen, Isabelle et al. “Genetic Evidence Supporting the Association of Protease and Protease Inhibitor Genes with Inflammatory Bowel Disease: A Systematic Review.” Ed. Marie-Pierre Dubé. PLoS ONE 6.9 (2011): e24106. PMC. Web. 6 Nov. 2016.
Loddo I and Romano C (2015) Inflammatory bowel disease: genetics, epigenetics, and pathogenesis. Front. Immunol. 6:551. doi: 10.3389/fimmu.2015.00551
Christodoulou K, Wiskin AE, Gibson J, Tapper W, Willis C, Afzal NA, Upstill-Goddard R, Holloway JW, Simpson MA, Beattie RM. Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes. Gut 2013;62:977–84. doi:10.1136/gutjnl-2011-301833