Inflammatory Bowel Disease: Genetics, Epigenetics, and Pathogenesis

Abstract

Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders characterized by chronic relapsing intestinal inflammation. Although etiology remains largely unknown, recent research has suggested that genetic factors, environment, microbiota, and immune response are involved in the pathogenesis. Epidemiological evidence for a genetic contribution is defined: 15% of patients with Crohn’s Disease (CD) have an affected family member with IBD, and twin studies for CD have shown 50% concordance in monozygotic twins compared to <10% in dizygotics. The most recent and largest genetic association studies, which employed genome-wide association data for over 75,000 patients and controls, identified 163 susceptibility loci for IBD. More recently, a trans-ethnic analysis, including over 20,000 individuals, identified an additional 38 new IBD loci. Although most cases are correlated with polygenic contribution toward genetic susceptibility, there is a spectrum of rare genetic disorders that can contribute to early-onset IBD (before 5 years) or very early onset IBD (before 2 years). Genetic variants that cause these disorders have a wide effect on gene function. These variants are so rare in allele frequency that the genetic signals are not detected in genome-wide association studies of patients with IBD. With recent advances in sequencing techniques, ~50 genetic disorders have been identified and associated with IBD-like immunopathology. Monogenic defects have been found to alter intestinal immune homeostasis through many mechanisms. Candidate gene resequencing should be carried out in early-onset patients in clinical practice. The evidence that genetic factors contribute in small part to disease pathogenesis confirms the important role of microbial and environmental factors. Epigenetic factors can mediate interactions between environment and genome. Epigenetic mechanisms could affect development and progression of IBD. Epigenomics is an emerging field, and future studies could provide new insight into the pathogenesis of IBD.

Intestinal microbiota, fecal microbiota transplantation, and inflammatory bowel disease

“…3,4 IBD is grouped into predominantly phenotypic patterns based on the location of inflammation: in Crohn's disease (CD), the inflammation can be in any part of the intestine, while in ulcerative colitis (UC) the inflammation is limited to the colon. In IBD, an abnormal intestinal microbiota (dysbiosis) is clearly associated with certain disease phenotypes, and may be a causal or synergistic factor in perpetuating chronic inflammation.…”

Hydroxymethylation Influences on Intestinal Epithelial Cells in Health and Disease

“…Speciically, smoking is protective in ulcerative colitis and patients may experience lares with cessation of smoking; whereas in Crohn's disease, smoking worsens disease [42][43][44]. Recent studies including the GWAS have identiied an important role for genetics as well as gene regulation and epigenetics in IBD [45,46]. To date the GWAS have identiied 163 loci that are associated with IBD; however, only approximately 10% of these loci are located in DNA coding regions suggesting an important role for gene regulation [47,48].…”

Targeted therapy of inflammatory bowel diseases: realities and prospects

“…Генетически-детерминированные нарушения врожден-ного иммунитета, ассоциированные с альтерацией процес-са рекогниции молекулярных структур кишечной микро-биоты (полиморфизмы генов NOD2/CARD15, TLR2, TLR4, TLR9) и аутофагии (полиморфизмы генов ATG16L1 и IRGM), были выявлены несколькими независимыми ПГАИ у паци-ентов с ВЗК [16][17][18]. Ряд других генов, которые были иден-тифицированы ПГАИ как факторы предрасположенности к ВЗК, отвечают за звенья адаптивного иммунитета, и в пер-вую очередь вектора дифференцировки Th17-лимфоцитов (полиморфизмы генов IL-23R, IL12B, JAK2 и STAT3) [17,19,20].…”