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IBD genetics focused on understanding susceptibility loci, therapeutic targets
With a steadily increasing prevalence, long-term disease burden and risk for mortality and morbidity, inflammatory bowel disease looms as a potential public health crisis.
Researchers continue to investigate the multifactorial etiology of this spectrum of autoimmune and inflammatory responses, manifested primarily as ulcerative colitis (UC) and Crohn’s disease. While environmental mechanisms play a role in inflammatory bowel disease (IBD), there is also a strong genetic component to these conditions. A review by Johan Van Limbergen, MD, FRCPCH, PhD, assistant professor and clinician scientist in the Department of Pediatrics at Dalhousie University and the Division of Pediatric Gastroenterology & Nutrition at IWK Health Centre in Halifax, Nova Scotia, Canada, and colleagues reported on the most recent data regarding the genetics of IBD.
The Immunochip Project
The Immunochip Project is the latest effort in the search for the genetic factors involved in IBD. The goal of the project is to replicate the top 2,000 independent correlation signals for each condition studied.
Autoimmune and inflammatory disease investigators specifically tailored the immunochip to include nearly 200,000 single-nucleotide polymorphisms (SNPs) pertaining to various autoimmune diseases and more than 700 small insertion-deletions. This project is intended to fine-map the 99 recognized IBD susceptibility loci, and will likely provide new information about the genetic commonalities with other autoimmune diseases, such as rheumatoid arthritis, psoriasis, ankylosing spondylitis and type 1 diabetes.
Familial studies of IBD
Studies of UC and CD in families have provided key findings that have facilitated large-scale genome-wide association studies (GWAS) on the genetic patterns of IBD. These findings include more disease similarity in twins with CD than those with UC; greater risk of IBD development among siblings of IBD sufferers than among the general population; and a high prevalence of IBD family history. This data has enabled researchers to estimate the extent to which IBD susceptibility is attributable to genetics. However, the validity of these family studies has been called into question, according to the review.
Familial IBD loci have also been found using nonparametric linkage analysis. The most replicated and confirmed loci in GWAS and the Immunochip project were IBD1, IBD3 and IBD5.
Analyzing IBD loci
Of the 163 identified IBD loci, two-thirds are shared between CD and UC. Researchers have also identified 30 loci specific to Crohn’s disease and 23 loci exclusive to UC. The majority of disease-specific loci have the same direction of effect as the disease to which they are not specific. Exceptions include PTPN22 and NOD2, which appear to be protective against UC. Based on the degree of shared genetic risk between CD and UC, it appears that most of the disease pathways of one condition also play a role in the other.
“These findings open up tremendous avenues for targeted development of new therapies in IBD, but might also be relevant to understanding how treatment of one immune-mediated disease can trigger development of another,” the researchers wrote. “This new avenue of understanding ‘shared’ susceptibility can be particularly important, as some of the most clinically relevant diseases to IBD clinicians are also showing the strongest enrichment of genetic risk overlap: ankylosing spondylitis, psoriasis, primary immunodeficiencies, and susceptibility to infectious diseases.”
Rare variants
Some of the first exome-sequencing studies in adult-onset IBD have indicated that only a small number of rare variants are involved in IBD. Along with rare mutations in NOD2, these studies have isolated rare variants in IL23R, PTPN22, CARD9, PRDM1 and NDP52.22, 25. This finding has subsequently resulted in a new focus in gene expression regulation. This provides a foundation for understanding how immune-mediated diseases can share common loci. Moreover, researchers are exploring new treatments that target IL-12–IL-23 signaling.
The role of autophagy
Studies have also established the role played by autophagy in the pathogenesis of IBD. Autophagy was first revealed to be involved in IBD after a nonsynonymous SNP association study revealed a strong signal of the T300A variant in ATG16L1. This association was subsequently confirmed in various GWAS and meta-analyses. Autophagy involves cellular mechanisms through which portions of the cytoplasm are delivered to the lysosome for breakdown in response to metabolic or infectious prompts. Currently, various autophagy-modulation drugs are slated for further study in IBD treatment. Mouse model studies, as well as studies on both healthy individuals and CD patients, have evaluated ATG16L1 function. In Atg16l1-deficient and hypomorphic mice, autophagy, Paneth-cell homeostasis and Il-1β secretion were found to be dependent on ATG16L1.
Leukocyte and chemotaxis homing
The researchers wrote that the homing of leukocytes to inflamed sites in IBD is an established obstacle to IBD treatment. Impairments in neutrophil chemotaxis and uncontrolled lymphocyte margination have been implicated in the pathogenesis of IBD. The genes responsible for homing of lymphocytes and chemotaxis have now been found on various IBD susceptibility loci, including integrins and chemokines or chemokine receptors. The discovery of progressive, multifocal leukoencephalopathy with the non-gut specific anti-alpha4 integrin, natalizumab (Tysabri, Biogen Idec), led to the high-priority development of gut-selective drug therapy. Additional molecules to target the lymphocyte homing mechanism are expected in coming years. The humanized antibody vedolizumab (Entyvio, Takeda), which targets the alpha 4 beta 7 integrin, has been evaluated in phase-3 studies for both CD and UC, and phase-1 data has been released for the humanized monoclonal antibody etrolizumab.
The future of genetic IBD study
According to the study researchers, the data revealed through exome and whole-genome sequencing should be balanced with new findings on gene regulation, analyses of specific cell types, and new information about the complicated environment of gut microbiota.
“International efforts are underway to assess the contribution of the known IBD susceptibility loci in populations of non-European ancestry,” the researchers wrote. “In years to come, these advances will hopefully increasingly affect patient care by offering the prospect of prediction of disease course and early intervention with genotype and microbiota-type targets.”
Disclosures: The researchers report no relevant financial disclosures.