Reviews and PerspectivesReviews in Basic and Clinical Gastroenterology and HepatologyBeyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics
Section snippets
Genetics in IBD: A Generation of Progress
In the past 25 years, there has been intense interest in identifying genetic and more recently epigenetic changes that relate to the pathogenesis of IBD. Few other complex diseases have been the subject of such extensive genetic and epigenetic research.
National consortia and subsequently large international collaborative research groups, such as the International IBD Genetics Consortium, have led the way in performing large-scale appraisals of the genome of patients with IBD (//www.ibdgenetics.org/
The Genetic Architecture of IBD
Early GWAS identified IBD loci common and unique to CD and UC.11 The latest data show the increasing proportion of loci common to both diseases, with relatively fewer CD- or UC-specific loci.9 Of the 163 identified loci, 110 are associated with both diseases, 30 are CD specific, and 23 are UC specific.9 Studies of gene loci shared by UC and CD may provide insight into their common pathogenic mechanisms. The T-helper (Th)17 and interleukin (IL)-12/IL-23 pathway is well established in the
CD-Specific Susceptibility Loci and Pathways
CD has a greater genetic component than that of UC, and several CD-specific susceptibility loci have been delineated. The latest genetic data increasingly highlight the relationship between the host innate immune system and the intestinal microbiota in CD. GWAS have indicated that intracellular bacterial processing by autophagy is an important pathogenic mechanism. Importantly, the association between CD and NOD2 has been consistently replicated at the genome-wide significance level18; NOD2 has
UC-Specific Susceptibility Loci and Pathways
Although UC susceptibility loci have primarily included genes that regulate intestinal epithelial barrier function, there is recent evidence that HLA variants are involved in the development of UC.9 HLA-DQA1 was the locus most strongly associated with UC (odds ratio, 1.44),with no corresponding increased risk in CD.9 The HLA class II genes are tremendously diverse and control antigen presentation to T cells; they have been implicated in other immune diseases.
Hepatocyte nuclear factor 4A (HNF4A)
Relationships With Other Diseases
Jostins et al reported that 70% of IBD loci overlap with loci associated with other complex immune diseases, such as IL23R variants associated with psoriasis and ankylosing spondylitis.26, 27, 28, 29 However, these polymorphisms sometimes have opposite effects in different diseases. For example, a variant of PTPN22 protects against CD but is a risk factor for type 1 diabetes and rheumatoid arthritis.30 Extraintestinal manifestations of IBD also share common loci, which may explain their
Current Agenda for Genetic Studies of IBD
Many of the IBD loci identified so far have not been accurately characterized or fine mapped, and the candidate genes commonly used to describe them are only putative. Moreover, the biological functions of their products, and their complex interactions, in most cases require delineation. Studies are under way to use the greater detail afforded by the ImmunoChip data to fine map loci, and functional studies are needed. Further work is required to determine how specific variants affect levels of
From the Environment to Genetics via Epigenetics
The challenge remains to measure patients’ duration, intensity, and frequency of exposure to the many environmental factors that potentially could contribute to IBD, making the environmental impact on disease difficult to disentangle.45 Epigenetic factors could mediate gene-environment interactions involved in pathogenesis. Epigenetic programming begins at fertilization and continues throughout life. Studies of Agouti mice and the offspring of post–World War II Dutch famine survivors revealed
What Is Epigenetics?
Epigenetics may be defined as mitotically heritable changes in gene function not explained by changes in the DNA sequence. Gene expression can be altered by changes to the structure and function of chromatin (Figure 2). The main epigenetic mechanisms include DNA methylation, histone modification, RNA interference, and the positioning of nucleosomes (which will not covered in depth in this review).
The epigenome can be regarded as both stable and plastic. The epigenome can be regarded as stable
DNA Methylation
Initial DNA methylation studies largely focused on the predisposition to cancer in IBD. DNA methylation changes in colonic epithelial cells that normally occur with aging are accelerated in IBD because of higher cell turnover in inflammation.80 Increased age-related DNA methylation, observed in colon cells of patients with colitis, could lead to genetic instability and development of cancer.80 Increased DNA methylation has been shown in dysplastic and the surrounding nondysplastic colon tissues
Interaction Between Genetics and Epigenetics in Complex Disease
An intriguing field of investigation is the relationship between genetic and epigenetic factors. There is evidence of colocalization of differentially methylated CpGs at predisposing SNPs identified at GWAS. In our own EWAS of CD, we showed enrichment of methylation changes within 50 kilobases from GWAS-identified susceptibility loci, including IL-19, IL-27, TNF, and NOD2.79 In a recent large methylation study of patients with rheumatoid arthritis, in 5 of 9 MHC genes, a specific genotype was
Clinical Implications
A number of potential clinical applications of epigenetics in diagnostics and therapeutics are receiving attention. The diagnostic applications of epigenetics include the use of biomarkers to confirm diagnosis, stratify disease course and response to chemotherapy, and predict development of cancer.122 Particularly pertinent for IBD, methylation changes in SFRP2, measured in fecal DNA samples, have been used to identify patients with colorectal cancer with approximately 75% sensitivity and
Therapeutics
Further studies of epigenetic factors associated with IBD could lead to new therapeutic strategies, whether they specifically target epigenetic mechanisms or affect the pathways they control. Pharmacologic agents that affect epigenetic processes include HDACi, HAT inhibitors, and DNMT inhibitors. However, these have not been tested in patients with IBD. HDACi were first licensed in the United States for treatment of T-cell lymphoma and are now being evaluated for inflammatory disorders such as
Conclusions
Great strides have been made in understanding the genetic basis for IBD, providing insight into new pathogenic mechanisms and expanding existing ones. Further studies are required to fine map the 163 known IBD susceptibility loci and determine how they contribute to disease risk. Epigenomics is an emerging field that adds an extra layer of complexity to genetic analyses. Epigenetic studies could provide exciting clues into the pathogenesis of IBD but, like genetics, are unlikely to address all
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Conflicts of interest The authors disclose no conflicts.
Funding N.T.V. is funded through the EU FP7 grant “IBD-BIOM,” and N.A.K. is funded through the Wellcome Trust.