Update on the genetics of inflammatory bowel disease

There is a general consensus that interplay of genetic and environmental factors leads to an overactive mucosal immune response, which mediates the tissue damage in inflammatory bowel disease. Ethnic aggregation of inflammatory bowel disease (particularly, increased incidence and prevalence in the Ashkenazim), familial aggregation of inflammatory bowel disease, and greater concordance for inflammatory bowel disease in monozygotic twins than dizygotic twins are 3 lines of evidence for a central role of genetic factors in the pathogenesis. The genetics of inflammatory bowel disease cannot be explained by simple Mendelian genetics; it is characterized by incomplete penetrance, multiple susceptibility loci and genetic heterogeneity. Unraveling the complex genetics of inflammatory bowel disease is a daunting challenge, but the perseverance of inflammatory bowel disease gene hunters has produced commendable results in recent years. Since 1996, the field of inflammatory bowel disease genetics has progressed from publication of the first systematic genome searches for inflammatory bowel disease susceptibility loci to the identification of Crohn disease-associated genetic variants in CARD15/NOD2. Strategies for finding additional inflammatory bowel disease genes include taking advantage of the greater resolution and power of linkage disequilibrium mapping, mapping by admixture disequilibrium in African-American and Hispanic-American populations, stratifying genetic analyses by genotypes at known inflammatory bowel disease loci, and refining inflammatory bowel disease phenotypes to reduce genetic heterogeneity and simplify the search for additional inflammatory bowel disease genes.     

Update on the genetics of inflammatory bowel disease

Crohn’s disease and ulcerative colitis are related genetic disorders. Epidemiologic studies suggest that both disorders are caused by a complex interplay of genetic and environmental factors. Genetic linkage studies identify the general chromosomal locations of disease susceptibility genes, and a number of genetic linkages have been reported in inflammatory bowel disease (IBD). Most notable among these linkage regions has been the linkage in the pericentromeric region of chromosome 16, IBD1, among families multiply affected with Crohn’s disease. Recent studies have established that at least three coding region variants in the Nod2 gene are responsible for the linkage findings here, and Nod2 therefore represents the first definitively established gene contributing to the pathogenesis of IBD. The implications of these findings for advancing our understanding of Crohn’s disease are discussed.     

炎症性肠病与骨质疏松研究进展

骨质疏松是炎症性肠病(IBD)患者常见但易被忽视的并发症之一.炎症性肠病患者骨质疏松的发病机制尚未完全明了,皮质类固醇激素的应用、炎性细胞因子的增加、维生素D的缺乏及遗传等众多因素均可能参与骨质疏松的发生.对于炎症性肠病患者并发骨质疏松者应及早诊断及治疗,早期干预可减轻IBD患者骨质疏松的发生与发展.     

The genetics of inflammatory bowel disease

The complex genetics of IBD is characterized by more than one susceptibility locus, genetic heterogeneity, incomplete penetrance, and probable gene-gene and gene-environment interactions. Functional candidate gene association studies during the past few decades have revealed only modest associations between IBD and genetic variants in the HLA genes and a limited number of other genes that are involved in immune regulation and the inflammatory response. Important advances in IBD genetics research have come about from systematic genome searches for IBD loci. The identification of Crohn's disease-associated NOD2 genetic variants that appear to alter the innate immune response to bacteria is a seminal finding that perhaps is the greatest advance toward understanding the pathogenesis of IBD in decades. The future discovery of other IBD genetic risk factors, facilitated by the completion of the human genome sequencing and annotation, may allow the development of better therapies, possibly including preventive therapies, for patients with Crohn's disease and ulcerative colitis.     

The genetics of inflammatory bowel disease

The inflammatory bowel diseases (IBD) comprise complex genetic disorders, with multiple contributing genes. Linkage studies have implicated several genomic regions as likely containing IBD susceptibility genes, with some observed uniquely in Crohn's disease (CD) or ulcerative colitis (UC), and others common to both disorders. The best replicated linkage region, IBD1, on chromosome 16q contains the CD susceptibility gene, NOD2/CARD15. NOD2/CARD15 is expressed in peripheral blood monocytes and is structurally related to the plant R proteins, which mediate host resistance to microbial pathogens. Three major coding region polymorphisms within NOD2/CARD15 have been highly associated with CD among patients of European descent. Having one copy of the risk alleles confers a 2-4-fold risk for developing CD, whereas double-dose carriage increases the risk 20-40-fold. All 3 major CD variants exhibit a deficit in NF-kappaB activation in response to bacterial components. Carriage of NOD2/CARD15 risk alleles is associated with ileal location, earlier disease onset, and stricturing phenotype. Other IBD genomic regions include IBD2 on chromosome 12q (observed more in UC), and IBD3, containing the major histocompatibility complex region. A short genomic region has been associated with CD on chromosome 5q, but the precise contributing gene is as yet unidentified. The characterization of additional IBD susceptibility genes could potentially lead to the identification of novel therapeutic agents for IBD, make possible a molecular reclassification of disease, and increase understanding of the contribution of environmental factors (notably, tobacco and the intestinal microbial milieu) to intestinal inflammation.     

The genetics of inflammatory bowel disease

Great progress in the understanding of the molecular genetics of inflammatory bowel disease (IBD) has been made over the last 10 years. Strong epidemiological evidence, based initially on concordance data in twin/family studies, led to the application of genome-wide linkage analysis involving multiply affected families and the identification of a number of susceptibility loci. Further characterization of the IBD1 locus on chromosome 16 led to the discovery of the NOD2/CARD15 gene as the first susceptibility gene in Crohn's disease for 2001. This landmark finding has led to a redirection of basic research in IBD with interest focused principally on regulation of the innate immune response and mucosal barrier function. Within the last year, the use of genome-wide association studies has provided new insights into primary pathogenetic mechanisms; several new genes such as the Interleukin-23 receptor (IL23R) and ATG16L1 (autophagy-related 16-like 1) genes are strongly implicated. Overall, these studies promise to change our fundamental understanding of IBD pathophysiology and to have implications for clinical practice.     

Clinical implications of inflammatory bowel disease genetics on phenotype

The genetic revolution has been with us for over a decade now. We have yet to see this impacting the care of patients except in a few rare examples. However, progress has been made in the field of inflammatory bowel disease (IBD) that could soon be translated to the bedside, both in terms of predicting the disease course as well as in the response to therapy. IBD traditionally has been classified as ulcerative colitis and Crohn's disease, with 10% of patients classified as having indeterminate colitis on the basis of clinical, radiologic, endoscopic, and histologic findings. However, this traditional view is now being challenged. Developments in genetics and serological markers, as well as an appreciation of the disease course, have led to an understanding that IBD is a heterogeneous group of diseases with some common genetic and environmental factors but different clinical manifestations in terms of disease behavior, location, and response to treatment. Data are now emerging that may allow us to more objectively select the correct therapy for the correct patient, rather than the current approach, which is based on clinical experience backed up by a less-than-perfect evidence base. In this article, we will review the evidence for this.     

Advances in the genetics of inflammatory bowel disease

Research efforts in the inflammatory bowel diseases have been uniquely successful in identifying genetic linkage regions likely containing susceptibility genes for Crohn’s disease and ulcerative colitis. In two of these regions, definitive gene associations have been established, namely for the NOD2/ CARD 15 gene on chromosome 16 (IBD1) and the OCTN1/ SLC22A4-OCT/SLC22A5 genes on chromosome 5q (IBD5), both conferring increased risk for developing Crohn’s disease. Recently, significant gene associations have been reported for additional genes, including DLG5, MDR1, and TLR4 as well. The NOD2/CARD15 gene mutations are associated with ileal disease location and a modestly earlier age of onset compared with NOD2/CARD15 wild-type Crohn’s disease patients. Future progress in the genetics of inflammatory bowel disease will likely involve systematic phenotyping, including the incorporation of clinical subtypes and novel biomarkers. The ultimate goal of genetic research in inflammatory bowel disease is to identify the earliest biologic pathways that are altered, resulting in disease pathogenesis. Identification of these key pathways will potentially highlight novel therapeutic targets.     

Pediatric inflammatory bowel disease: clinical and molecular genetics

Pediatric-onset inflammatory bowel disease (IBD) is characterized by distinct phenotypic differences compared to adult-onset IBD. This raises the question whether early (pediatric) onset IBD represents the same disease process occurring in adults but merely at an earlier age or does IBD in children have a very different etiology and pathogenesis but with the same clinical presentation as adults. The use of techniques such as whole genome association studies to perform broad, unbiased screening for the contributions of common genetic variations to complex disease has rapidly assisted in the identification of several novel susceptibility loci associated with pediatric-onset Crohn's disease such as IL23R and ATG16L1. These genes join the already confirmed IBD susceptibility genes such as NOD2/CARD15, IBD5, and DLG5. Therefore, there is hope that advances in the field of clinical and molecular genetics will assist in answering the fundamental question of whether pediatric IBD has a different etiology and pathogenesis compared to adult IBD. This review examines the current status of clinical and molecular genetics of pediatric IBD, and highlights the differences between pediatric and adult IBD in disease phenotypes and genotypes. Finally, the future directions of genetic investigations in pediatric IBD are discussed.     

Update on inflammatory bowel disease in patients with primary sclerosing cholangitis

Patients with primary sclerosing cholangitis(PSC) complicated by inflammatory bowel disease(IBD) represent a distinct subset of patients with unique characteristics,which have serious clinical implications.The aim of this literature review was to shed light to the obscure clinical and molecular aspects of the two diseases combined utilizing current data available and putting issues of diagnosis and treatment into perspective.The prevalence of IBD,mainly ulcerative colitis in PSC patients is estimated to be 21%-80%,dependent on screening programs and nationality.PSC-associated colitis is likely to be extensive,characterized by rectal sparing,backwash ileitis,and generally mild symptoms.It is also more likely to progress to colorectal malignancy,making it imperative for clinicians to maintain a high level of suspicion when tackling PSC patients.There is no optimal surveillance strategy but current guidelines advocate that colonoscopy is necessary at the time of PSC diagnosis with annual endoscopic follow-up.Random biopsies have been criticized and a shift towards targeted biopsies using chromoendoscopy,laser endomicroscopy and narrow-band imaging has been noted.Techniques directed towards genetic mutations instead of histological abnormalities hold promise for easier,more accurate diagnosis of dysplastic lesions.Chemopreventive measures against colorectal cancer have been sought in these patients.Ursodeoxycholic acid seemed promising at first but subsequent studies yielded conflicting results showing anticarcinogenic effects in low doses(8-15 mg/kg per day) and carcinogenic properties in high doses(15-30 mg/kg per day).     

肠道平滑肌动力与炎症性肠病研究进展

肠道平滑肌动力改变与炎症性肠病(IBD)的发病关系得到医学界的重视,并逐渐成为IBD发病机制研究的热点.肠道运动的异常和神经递质的失衡在IBD的发生和进展过程中起了重要作用;白细胞介素能在一定程度上反映肠道运动功能变化.因此,恢复神经递质的失衡并重建肠道动力平衡的策略在IBD治疗过程中有良好的应用前景.     

Update on medical management of inflammatory bowel disease: ulcerative colitis

Significant advances have been made regarding our understanding of the etiopathogenesis of inflammatory bowel disease. This review focuses on the most recent applications of medical therapy for ulcerative colitis. Therapeutic approaches continue to evolve regarding inductive and maintenance strategies with oral and topical aminosalicylates, systemic and non-systemic corticosteroids, and cyclosporine and alternative immunomodulators. As further investigations continue to discern microbiological and immunoinflammatory targets, future therapies may include both probiotics and novel biological agents.     

Update on therapeutic management of spondyloarthritis associated with inflammatory bowel disease

Clinical Rheumatology - Management of spondyloarthritis (SpA) in patients with inflammatory bowel disease (IBD) remains a challenging task that requires multidisciplinary collaboration. Separate...     

Update of fecal markers of inflammation in inflammatory bowel disease

The diagnosis, prognosis, and assessment of disease activity of inflammatory bowel disease (IBD) require investigating clinical, radiological, and histological criteria, as well as serum inflammatory markers. However, a range of fecal inflammatory markers now appears to have the potential to greatly assist in these processes. Calprotectin, a prominent neutrophil protein, was identified two decades ago as a potentially revolutionary marker for IBD. Following this discovery, numerous additional markers, including S100A12, lactoferrin, and M2-pyruvate kinase, have also been suggested as novel markers of IBD. In the present study, we provide an up-to-date review of fecal markers of IBD, and further, provide a novel analysis of each of these fecal markers in severe ulcerative colitis and compare their expression pattern in contrast to calprotectin.