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• W2162217523 abstract "In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD. In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD. The inflammatory bowel diseases (IBDs) Crohn’s disease (CD) and ulcerative colitis (UC) are an important health problem, with an incidence among European adults of 12.7 and 24.3 per 100,000 person-years, respectively, and a prevalence of 0.5% to 1.0%.1Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (2863) Google Scholar Moreover, the incidence of IBD is increasing among adults and children and in the developed and developing world.1Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (2863) Google Scholar, 2Henderson P. Hansen R. Cameron F.L. et al.Rising incidence of pediatric inflammatory bowel disease in Scotland.Inflamm Bowel Dis. 2012; 18: 999-1005Crossref PubMed Scopus (130) Google Scholar, 3Benchimol E.I. Guttmann A. Griffiths A.M. et al.Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data.Gut. 2009; 58: 1490-1497Crossref PubMed Scopus (264) Google Scholar, 4Ng S.C. Bernstein C.N. Vatn M.H. et al.Geographical variability and environmental risk factors in inflammatory bowel disease.Gut. 2013; 62: 630-649Crossref PubMed Scopus (332) Google Scholar, 5Gunesh S. Thomas G.A. Williams G.T. et al.The incidence of Crohn’s disease in Cardiff over the last 75 years: an update for 1996-2005.Aliment Pharmacol Ther. 2008; 27: 211-219Crossref PubMed Scopus (0) Google Scholar In the United Kingdom, IBDs cost the National Health Service approximately £720 million (approximately $1.1 billion) per annum.6IBD Standards Group UKQuality care cervice standards for the healthcare of people who have inflammatory bowel disease.2009http://www.ibdstandards.org.uk/ibd-standards.aspGoogle Scholar, 7van der Valk M.E. Mangen M.-J.J. Leenders M. et al.Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study.Gut. 2012 Nov 7; ([Epub ahead of print])Google Scholar The pathogenesis of IBD is believed to involve an aberrant immune response to intestinal microbiota in genetically susceptible individuals.8Xavier R.J. Podolsky D.K. Unravelling the pathogenesis of inflammatory bowel disease.Nature. 2007; 448: 427-434Crossref PubMed Scopus (2905) Google Scholar Genetic studies have provided many candidate loci in the past decade, and the innate and acquired immune responses have been implicated in pathogenesis. However, identified genetic factors account for only a modest proportion of the disease variance: 13.6% for CD and 7.5% for UC.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar These figures highlight the need for critical evaluation of genetic discoveries to date and indicate the importance of environmental factors in the pathogenesis of IBD; in addition, the intriguing possibility arises that epigenetics may partially account for the “hidden heritability” in IBD. We review recent genetic discoveries in IBD and introduce readers to epigenetic factors that could be involved in pathogenesis. 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 (http://www.ibdgenetics.org/). The assumption-free approach of genome-wide association studies (GWAS) has helped to support established etiologic roles of the innate and acquired immune system in IBD and identified interesting new mechanisms such as autophagy.10Van Limbergen J. Stevens C. Nimmo E.R. et al.Autophagy: from basic science to clinical application.Mucosal Immunol. 2009; 2: 315-330Crossref PubMed Scopus (0) Google Scholar Findings from the past 25 years of genetic discovery in IBD have been put into context by the latest meta-analysis of the GWAS and ImmunoChip data.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar The ImmunoChip (Illumina, Inc, San Diego, CA) was developed following GWAS of IBD and other immune diseases; it contains 200,000 single nucleotide polymorphisms (SNPs) relevant to IBD and other immune-mediated diseases. The aims of the ImmunoChip experiments are to replicate and fine map the known IBD susceptibility loci and to identify common links with other immune disorders. The meta-analysis comprised more than 75,000 cases and controls and more than 1.23 million SNPs from several centers worldwide. It identified a further 64 loci, bringing the total number of IBD-associated loci to 163; this is significantly more than for any other complex disease.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar Early GWAS identified IBD loci common and unique to CD and UC.11Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease.Nature. 2011; 474: 307-317Crossref PubMed Scopus (1432) Google Scholar The latest data show the increasing proportion of loci common to both diseases, with relatively fewer CD- or UC-specific loci.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar Of the 163 identified loci, 110 are associated with both diseases, 30 are CD specific, and 23 are UC specific.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar 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 pathogenesis of IBD, with susceptibility gene loci IL23R, IL12B, JAK2, and STAT3 identified in both UC and CD.12Anderson C.A. Boucher G. Lees C.W. et al.Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.Nat Genet. 2011; 43: 246-252Crossref PubMed Scopus (958) Google Scholar, 13Brand S. Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease.Gut. 2009; 58: 1152-1167Crossref PubMed Scopus (0) Google Scholar Variants in IL12B, which encodes the p40 subunit of IL-12 and IL-23, have been associated with IBD and other immune disorders. Defects in the function of IL-10, an immunosuppressive cytokine, have also been associated with CD and UC.14Franke A. Balschun T. Karlsen T.H. et al.Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility.Nat Genet. 2008; 40: 1319-1323Crossref PubMed Scopus (460) Google Scholar, 15Franke A. Mcgovern D.P.B. Barrett J.C. et al.Meta-analysis increases to 71 the tally of confirmed Crohn’s disease susceptibility loci.Nat Genet. 2010; 42: 1118-1125Crossref PubMed Scopus (0) Google Scholar A severe, childhood-onset, CD-like form of enterocolitis is associated with rare mutations in IL10R. However, this disorder could be a separate entity from idiopathic IBD.16Glocker E.-O. Kotlarz D. Boztug K. et al.Inflammatory bowel disease and mutations affecting the interleukin-10 receptor.N Engl J Med. 2009; 361: 2033-2045Crossref PubMed Scopus (961) Google Scholar, 17Glocker E.-O. Frede N. Perro M. et al.Infant colitis—it’s in the genes.Lancet. 2010; 376: 1272Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar Other susceptibility genes that regulate immune function include CARD9, IL1R2, REL, SMAD3, and PRDM1.12Anderson C.A. Boucher G. Lees C.W. et al.Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.Nat Genet. 2011; 43: 246-252Crossref PubMed Scopus (958) Google Scholar Interestingly, the well-established CD risk variants of NOD2 and PTPN22 appear to protect against UC. 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 level18Barrett J.C. Hansoul S. Nicolae D.L. et al.Genome-wide association defines more than thirty distinct susceptibility loci for Crohn’s disease.Nat Genet. 2009; 40: 955-962Crossref Scopus (0) Google Scholar; NOD2 has been mechanistically linked with autophagy.19Cooney R. Baker J. Brain O. et al.NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation.Nat Med. 2010; 16: 90-97Crossref PubMed Scopus (772) Google Scholar, 20Travassos L.H. Carneiro L.A.M. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (937) Google Scholar Cigarette smoking, a strong environmental factor in risk of CD, might affect NOD2 function.21Aldhous M.C. Soo K. Stark L.A. et al.Cigarette smoke extract (CSE) delays NOD2 expression and affects NOD2/RIPK2 interactions in intestinal epithelial cells.PloS One. 2011; 6: e24715Crossref PubMed Scopus (0) Google Scholar Furthermore, the product of the CD susceptibility gene ATG16L1 is recruited to the plasma membrane by NOD2, where it initiates bacterial internalization by autophagosomes.15Franke A. Mcgovern D.P.B. Barrett J.C. et al.Meta-analysis increases to 71 the tally of confirmed Crohn’s disease susceptibility loci.Nat Genet. 2010; 42: 1118-1125Crossref PubMed Scopus (0) Google Scholar, 18Barrett J.C. Hansoul S. Nicolae D.L. et al.Genome-wide association defines more than thirty distinct susceptibility loci for Crohn’s disease.Nat Genet. 2009; 40: 955-962Crossref Scopus (0) Google Scholar, 20Travassos L.H. Carneiro L.A.M. Ramjeet M. et al.Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry.Nat Immunol. 2010; 11: 55-62Crossref PubMed Scopus (937) Google Scholar Another gene involved in autophagy-induced bacterial killing is IRGM. CD-associated polymorphisms in IRGM lead to reduced protein expression. A different SNP of IRGM protects against Mycobacterium tuberculosis.22Cho J.H. Brant S.R. Recent insights into the genetics of inflammatory bowel disease.Gastroenterology. 2011; 140: 1704-1712Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 23Intemann C.D. Thye T. Niemann S. et al.Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains.PLoS Pathog. 2009; 5: e1000577Crossref PubMed Scopus (0) Google Scholar The most recent data from ImmunoChip studies indicated an overlap between IBD loci and complex mycobacterial disease loci9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar; 7 CD susceptibility genes overlap with leprosy susceptibility genes, and 6 mycobacterium susceptibility genes overlap with IBD loci. However, for several of these diseases, the genetic associations have opposite effects.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar Genes involved in the host response to mycobacteria that were previously associated with CD include CARD9 and LTA.11Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease.Nature. 2011; 474: 307-317Crossref PubMed Scopus (1432) Google Scholar, 15Franke A. Mcgovern D.P.B. Barrett J.C. et al.Meta-analysis increases to 71 the tally of confirmed Crohn’s disease susceptibility loci.Nat Genet. 2010; 42: 1118-1125Crossref PubMed Scopus (0) Google Scholar Other CD-specific loci identified related to the immune system include PTPN22, IL2RA, IL27, TNFSF11, and VAMP3.15Franke A. Mcgovern D.P.B. Barrett J.C. et al.Meta-analysis increases to 71 the tally of confirmed Crohn’s disease susceptibility loci.Nat Genet. 2010; 42: 1118-1125Crossref PubMed Scopus (0) Google Scholar, 18Barrett J.C. Hansoul S. Nicolae D.L. et al.Genome-wide association defines more than thirty distinct susceptibility loci for Crohn’s disease.Nat Genet. 2009; 40: 955-962Crossref Scopus (0) Google Scholar 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.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar HLA-DQA1 was the locus most strongly associated with UC (odds ratio, 1.44),with no corresponding increased risk in CD.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar 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) regulates expression of cell junction proteins in the intestinal epithelial barrier; variants have been associated with UC and with colorectal cancer, a complication of chronic inflammation in patients with IBD.24Barrett J.C. Lee J.C. Lees C.W. et al.Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.Nat Genet. 2009; 41: 1330-1334Crossref PubMed Scopus (372) Google Scholar Rare SNPs at the HNF4A gene locus, not implicated in UC, are associated with maturity-onset diabetes, inherited in an autosomal dominant fashion.25Yamagata K. Furuta H. Oda N. et al.Mutations in the hepatocyte nuclear factor-4gene in maturity-onset diabetes of the young (MODY1).Nature. 1996; 384: 458-460Crossref PubMed Scopus (0) Google Scholar Other UC-associated genes that affect epithelial barrier function include CHD1, which encodes E-cadherin, and LAMB1, which encodes the lamina β subunit 1. Many UC risk alleles encode cytokines and inflammatory mediators, including tumor necrosis factor (TNF) receptor superfamily members (TNFRSF14, TNFRSF9), ILs, and IL receptors (IL1R2, IL8Ra/RB, IL7R).12Anderson C.A. Boucher G. Lees C.W. et al.Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.Nat Genet. 2011; 43: 246-252Crossref PubMed Scopus (958) Google Scholar 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.26Cargill M. Schrodi S.J. Chang M. et al.A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.Am J Hum Genet. 2007; 80: 273-290Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar, 27Burton P. Clayton D. Cardon L. et al.Association scan of 14,500 nsSNPs in four common diseases identifies variants involved in autoimmunity.Nat Genet. 2009; 39: 1329-1337Crossref Scopus (0) Google Scholar, 28Cho J.H. Gregersen P.K. Genomics and the multifactorial nature of human autoimmune disease.N Engl J Med. 2011; 365: 1612-1623Crossref PubMed Scopus (0) Google Scholar, 29Lees C.W. Barrett J.C. Parkes M. et al.New IBD genetics: common pathways with other diseases.Gut. 2011; 60: 1739-1753Crossref PubMed Scopus (424) Google Scholar 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.30Wang K. Baldassano R. Zhang H. et al.Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects.Hum Mol Genet. 2010; 19: 2059-2067Crossref PubMed Scopus (129) Google Scholar Extraintestinal manifestations of IBD also share common loci, which may explain their co-occurrence. For example, variants of REL, IL2, and CARD9 are associated with UC and primary sclerosing cholangitis.11Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease.Nature. 2011; 474: 307-317Crossref PubMed Scopus (1432) Google Scholar, 31Muriboberg K. Melum E. Folseraas T. et al.Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL and CARD9.Hepatology. 2012; 53: 1977-1985Google Scholar 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 messenger RNA (mRNA) and consequently protein, which could provide further insight into mechanisms of pathogenesis. This is likely to take considerable time; NOD2 was identified more than 10 years ago, and there is still uncertainty about its function.29Lees C.W. Barrett J.C. Parkes M. et al.New IBD genetics: common pathways with other diseases.Gut. 2011; 60: 1739-1753Crossref PubMed Scopus (424) Google Scholar GWAS have excelled in identifying moderate-risk genetic variants with at least 5% prevalence in the population. Novel approaches are needed to discover lower-prevalence variants with higher effect size. Whole-exome sequencing, which covers only coding areas of the genome, costs less than whole-genome sequencing and tends to afford higher-depth coverage and therefore greater certainty about novel discoveries. It has been successfully used to identify single mutations in very early-onset IBD32Worthey E.A. Mayer A.N. Syverson G.D. et al.Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.Genet Med. 2011; 13: 255-262Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar and is perhaps most likely to produce results in individuals with a strong family history or early age of disease onset. However, many polymorphisms that affect disease susceptibility are located in noncoding areas of the genome; the ENCODE project has highlighted the importance of noncoding regions in disease risk.33Dunham I. Kundaje A. Aldred S.F. et al.An integrated encyclopedia of DNA elements in the human genome.Nature. 2012; 489: 57-74Crossref PubMed Scopus (9436) Google Scholar Exome sequencing and whole-genome sequencing are each under way, with large-scale endeavors at the Sanger Centre likely to report results in mid-2013 (http://www.ibdresearch.co.uk/). Other researchers are looking for associations between specific genotypes and disease phenotypes. To date, NOD2 mutations have been associated with stricturing ileal CD, and DRB1*0103 has been associated with severe extensive UC.34Ahmad T. Armuzzi A. Bunce M. et al.The molecular classification of the clinical manifestations of Crohn’s disease.Gastroenterology. 2002; 122: 854-866Abstract Full Text Full Text PDF PubMed Google Scholar, 35Futami S. Aoyama N. Honsako Y. et al.HLA-DRB1*1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression.Dig Dis Sci. 1995; 40: 814-818Crossref PubMed Scopus (0) Google Scholar, 36Lesage S. Zouali H. Cézard J.-P. et al.CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.Am J Hum Genet. 2002; 70: 845-857Abstract Full Text Full Text PDF PubMed Scopus (833) Google Scholar The International IBD Genetics Consortium recently presented preliminary data from the core phenotyping project, which used ImmunoChip data to identify genetic factors that correspond to disease phenotypes. The International IBD Genetics Consortium confirmed the associations of variants of NOD2 and HLA with CD and UC, respectively, as well as associated HLA variants with location of CD and reported the effects of NOD2 and HLA genotypes on age of disease onset.37Lees C.W. Characterization of the ∼40,000 patient cohort of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC).J Crohn’s Colitis. 2013; 7: S4Abstract Full Text PDF Google Scholar Most IBD genetic analyses have been performed in the white populations of Northern Europe and America. More recently, there has been a push to expand this work to other ethnic populations.38Brant S.R. Promises, delivery, and challenges of inflammatory bowel disease risk gene discovery.Clin Gastroenterol Hepatol. 2012; 11: 22-26Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar IBD-associated variants of NOD2, for example, are less prevalent in black populations, and CD-associated mutations have not been detected in Asian or Sub-Saharan African populations.39Dassopoulos T. Nguyen G.C. Talor M.V. et al.NOD2 mutations and anti-Saccharomyces cerevisiae antibodies are risk factors for Crohn’s disease in African Americans.Am J Gastroenterol. 2010; 105: 378-386Crossref PubMed Scopus (24) Google Scholar, 40Inoue N. Lack of common NOD2 variants in Japanese patients with Crohn’s disease.Gastroenterology. 2002; 123: 86-91Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Pharmacogenomics, the study of how genomic factors affect the efficacy, tolerability, and side effects of a therapeutic agent, remains high on the research agenda. Patients are evaluated for thiopurine S-methyltransferase (encoded by TPMT) genotype and phenotyping before initiation of thiopurine therapy is recommended by the US Food and Drug Administration.41US Food and Drug AdministrationImuran (azathioprine) product information.[email protected]Date: 2011Google Scholar, 42Roberts R.L. Barclay M.L. Current relevance of pharmacogenetics in immunomodulation treatment for Crohn’s disease.J Gastroenterol Hepatol. 2012; 27: 1546-1554Crossref PubMed Scopus (0) Google Scholar There are ongoing attempts to predict patients’ response to other agents based on genetic factors. Studies supported by the Serious Adverse Events Consortium aim to predict mesalamine-induced nephrotoxicity (http://www.ibdresearch.co.uk/5asa/) and serious complications of anti-TNF therapies and thiopurines (http://www.ibdresearch.co.uk/pred4/). A main goal of IBD research is to develop disease-specific therapeutics. Many researchers are developing reagents to alter activities of genes and pathways identified through GWAS, and the IL-12/IL-23 signaling pathway is one promising target. Ustekinumab, a monoclonal antibody that binds to the shared p40 subunit encoded by IL12B, has undergone phase 2b induction and maintenance trials in patients with CD.43Sandborn W.J. Gasink C. Gao L.-L. et al.Ustekinumab induction and maintenance therapy in refractory Crohn’s disease.N Engl J Med. 2012; 367: 1519-1528Crossref PubMed Scopus (708) Google Scholar Apilimod mesylate, briakinumab (ABT-874), and SCH-900222, also target components of the IL-12/IL-23 signaling pathway, and are currently under evaluation.44Danese S. New therapies for inflammatory bowel disease: from the bench to the bedside.Gut. 2012; 61: 918-932Crossref PubMed Scopus (216) Google Scholar 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.45Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases.Nature. 2010; 465: 721-727Crossref PubMed Scopus (467) Google Scholar 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 how the environment can affect epigenetic factors. Dietary intake during pregnancy was shown to affect the epigenetic reprogramming step in offspring during early development, an effect that persisted for up to 2 generations.46Morgan H.D. Sutherland H.G.E. Martin D.I.K. et al.Epigenetic inheritance at the agouti locus in the mouse.Nat Genet. 2006; 23: 314-318Crossref Scopus (1024) Google Scholar, 47Schaible T.D. Harris R.A. Dowd S.E. et al.Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes.Hum Mol Genet. 2011; 20: 1687-1696Crossref PubMed Scopus (99) Google Scholar, 48Waterland R.A. Jirtle R.L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation.Mol Cell Biol. 2003; 23: 5293-5300Crossref PubMed Scopus (1465) Google Scholar, 49Tobi E.W. Lumey L.H. Talens R.P. et al.DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific.Hum Mol Genet. 2009; 18: 4046-4053Crossref PubMed Scopus (791) Google Scholar, 50Heijmans B.T. Tobi E.W. Lumey L.H. et al.Archive of the prenatal environment.Epigenetics. 2009; 4: 526-531Crossref PubMed Scopus (0) Google Scholar Moreover, there is evidence for acquired epigenetic changes with aging caused by a range of environmental factors.51Relton C.L. Davey Smith G. Epigenetic epidemiology of common complex disease: prospects for prediction, prevention, and treatment.PLoS Med. 2010; 7: e1000356Crossref PubMed Scopus (0) Google Scholar Epigenetics could therefore play a central role in the pathogenesis of IBD and other diseases, affecting interactions among genetic and environmental factors such as the intestinal microbiome (Figure 1). In IBD research, several key developments in molecular studies have led us from genetics to explore epigenetics. GWAS have identified key epigenetic regulatory enzymes such as DNA methyltransferase (DNMT) 3a and more recently DNMT3b as CD susceptibility genes.9Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 490: 119-124Crossref Scopus (0) Google Scholar, 15Franke A. Mcgovern D.P.B. Barrett J.C. et al.Meta-analysis increases to 71 the tally of confirmed Crohn’s disease susceptibility loci.Nat Genet. 2010; 42: 1118-1125Crossref PubMed Scopus (0) Google Scholar Dendritic cells that express CD-associated variants of NOD2 fail to up-regulate microRNA (miR) clusters that regulate Th1 and Th17 cell–mediated immune responses.52Brain O. Allan P. Pichulik T. et al.NOD2 regulation of micrornas.Gut. 2011; 60 (A37): A37Crossref Google Scholar Epigenetic mechanisms have also been shown to regulate the immune system. For example, differentiation of Th2 cells requires epigenetic silencing of the IFNG locus.53Janson P.C.J. Winer" @default.
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• W2162217523 date "2013-08-01" @default.
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• W2162217523 title "Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics" @default.
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