Understanding the genetic makeup of inflammatory bowel disease (IBD) , including Crohn’s disease and ulcerative colitis has been a focus for over 20 years. Recent advancements, especially in genome-wide association studies have significantly expanded our understanding by identifying over 200 genes associated with the condition. As our knowledge grows, so does the range of medications available for IBD treatment. However, this abundance of options complicates treatment decisions , many patients still struggle with the disease and may not respond well to treatment over time. Despite the progress, personalized treatment strategies based on genetic information are on the horizon. Genetic testing has been explored as a tool to guide treatment decisions such as identifying specific gene variations before starting certain medications. Yet, despite the identification of numerous risk genes their impact on treatment strategies and disease outcomes remains limited. In this review, we delve into the genetic basis of IBD by highlighting recent breakthroughs and their potential implications for treatment decisions.
Defining Shift in IBD Epidemiology
Background of Inflammatory Bowel Disease in Different Regions
Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease (CD), has long been associated primarily with people of European descent in Western industrialized nations. Occasional cases of UC have been reported in South Asia and South-east Asia but CD has been considered rare in these regions.
Changing Trends in India
However, in the past two decades, India has found itself at a crossroads epidemiologically. Not only are infectious diseases prevalent, but diseases previously thought to be exclusive to the Western world including IBD are also emerging. Despite questions about the rarity of IBD in India dating back over 50 years, the lack of comprehensive epidemiological studies has prevented confirmation of this observation.
Challenges in Studying IBD Epidemiology
Understanding the epidemiology of IBD in these regions faces numerous challenges. Limited access to healthcare, reliance on hospital-based studies, absence of standardized case definitions, lack of relevant databases , and registries and insufficient prospective data collection all contribute to the difficulty. Hospital-based studies, while convenient may underestimate the true incidence and exaggerate the severity of these supposedly "rare" diseases.
Unraveling the Mystery of a Rare Inflammatory Disease
Insight from Genetic and Immunological Research
Exploring the genetic and immunological aspects of an unknown inflammatory disease in an adult patient has provided valuable insights into the origins of such disorders. This research breakthrough led to the successful implementation of targeted therapy for the patient.
Discoveries by Leuven Researchers
Researchers from Leuven have elucidated a fascinating mechanism involving genetic mutations that contribute to this rare condition. Their findings recently published in the prestigious New England Journal of Medicine shed light on the underlying complexities of the disorder.
Understanding Auto-inflammatory Disorders
Auto-inflammatory disorders are complicated conditions characterized by inflammatory responses and fever triggered by an overactive immune system. These inflammations can occur spontaneously without any apparent external trigger, hence the term "auto-inflammation." While some cases indicate symptoms from childhood due to underlying genetic abnormalities, the understanding of auto-inflammation in adulthood remains limited.
New Insights into Adult-Onset Auto-inflammation
Leuven doctors and researchers have unveiled a novel mechanism that may explain the occurrence of auto-inflammation in adults. Through extensive genetic and immunological analyses of a patient with an unusual clinical presentation, they identified a mutation in a gene associated with auto-inflammatory responses (NLRC4). Remarkably, this mutation was only present in a subset of cells and manifested in adulthood. Further investigation revealed that the progression of the disease was fueled by a second mutation in TET2, leading to an increase in mutant cells over time. This groundbreaking discovery highlights the intricate interplay between genetic mutations and the onset of inflammatory diseases in adulthood.
Navigating the Role of a Protein Complex in Genetic Inflammatory Disease
A groundbreaking study conducted by a team of researchers led by Dr. Hirotsugu Oda from the University of Cologne's CECAD Cluster of Excellence for Ageing Research has shed light on the crucial role of a specific protein complex in certain types of immunological dysregulation. This discovery carries significant implications for potential therapeutic interventions aimed at mitigating auto-inflammatory conditions and restoring the compromised immune systems of individuals affected by a genetic malfunction of this protein complex.
The study titled "Biallelic human SHARPIN loss of function produces autoinflammation and immunodeficiency," published in the prestigious journal Nature Immunology unveils the pivotal role of LUBAC, the linear ubiquitin assembly complex composed of HOIP, HOIL-1, and SHARPIN proteins in maintaining immune homeostasis. While previous research on animal models has highlighted the severe dermatitis resulting from SHARPIN loss, its specific implications in human health have remained indescribable until now.
For the first time, the research team identified two human subjects with SHARPIN deficiency exhibiting symptoms of autoinflammation and immunodeficiency, although without the dermatological issues observed in animal models. Further investigation revealed a compromised canonical NF-kB response pathway crucial for immune response along with sensitive vulnerability to cell death mediated by TNF superfamily members. Remarkably, treatment with anti-TNF therapies led to the complete resolution of autoinflammation at both cellular and clinical levels in one SHARPIN-deficient individual.
This study emphasises the critical role of unchecked cell death in human genetic inflammatory diseases introducing SHARPIN deficiency as a new member of such disorders termed "inborn errors of cell death." Initiated at Dr. Dan Kastner's lab at the National Institutes of Health (NIH) in the USA, the research also explained the genetic basis of SHARPIN deficiency in patients experiencing unexplained fever episodes, arthritis, colitis and immunodeficiency.
The findings further revealed an increased tendency for cell death in patient cells leading to diminished development of lymphoid germinal centres critical for immune system maturation and antibody production. Dr. Oda emphasized the importance of LUBAC in safeguarding against immune dysregulation and highlighted the transformative potential of novel therapeutic strategies targeting this molecular pathway.
The study's impact extends beyond the realm of scientific discovery offering hope to patients like one wheelchair-bound individual whose life has been dramatically improved by targeted therapy based on genetic diagnosis. Dr. Oda's dual role as a clinician and scientist highlights the physical benefits of translating research findings into clinical practice and ultimately enhancing patient outcomes and quality of life.
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