Digestive System Disease

Digestive system diseases encompass a wide range of conditions that affect the organs responsible for digestion and nutrient absorption, including the esophagus, stomach, small and large intestines, liver, pancreas, and gallbladder. These diseases can lead to significant discomfort, impaired quality of life, and in some cases, severe complications. Among the most well-known are inflammatory bowel diseases (IBD), such as Crohn’s Disease (CD) and Ulcerative Colitis (UC), which are chronic inflammatory conditions of the gastrointestinal tract^[1].

The biological basis of many digestive system diseases, particularly complex conditions like IBD, involves a delicate interplay between an individual’s genetic makeup and environmental factors. Research indicates that these are complex trait diseases where each contributing factor may have a relatively modest effect on disease risk. For instance, strong evidence suggests a central role for the enteric microflora in the initiation and maintenance of IBD^[1]. Genetically, specific variants have been identified as susceptibility loci. Key examples include variants in the CARD15 gene (also known as NOD2) on chromosome 16q12 and the IBD5 haplotype on chromosome 5q31, which spans genes like SLC22A4 and SLC22A5 ^[2]. CD and UC are considered related disorders that share some genetic susceptibilities but also differ at others. More recently, genome-wide association (GWA) studies have expanded this understanding, identifying other replicated candidate genes and loci such as IL23R, ATG16L1, and a region on 5p13.1 near the PTGER4 gene ^[3]. The nature of these genes suggests a critical role for the innate immune response and the body’s ability to handle intracellular bacteria in the development of CD ^[3].

Clinically, digestive system diseases present with diverse phenotypes, even within the same condition. For example, CD and UC vary considerably among individuals regarding sites of inflammation, disease behavior (e.g., stricturing or penetrating), severity, and extraintestinal manifestations. Genetic factors appear to influence these variations;CARD15 mutations, for example, are a greater risk factor for ileal CD and stricturing behavior. Understanding these genetic underpinnings is crucial for developing personalized diagnostic approaches and therapeutic strategies.

The social importance of digestive system diseases is substantial. They impose a significant burden on affected individuals, impacting their daily lives, work, and social interactions. They also contribute to a considerable strain on healthcare systems due to chronic management, hospitalizations, and surgical interventions. Ongoing research, including large-scale GWA studies, aims to identify additional genetic risk factors, even those imparting only moderate increases in risk ^[4]. This continuous effort is vital for unraveling the full genetic architecture of these diseases, paving the way for improved prevention, diagnosis, and treatment options that can alleviate suffering and enhance public health.

Limitations

While genetic studies have significantly advanced the understanding of digestive system disease, several limitations inherent to the methodology and scope of current research warrant careful consideration when interpreting findings. These constraints affect the comprehensiveness of identified genetic associations and their generalizability across diverse populations.

Methodological and Statistical Power Constraints

Genome-wide association studies (GWAS) are subject to limitations in statistical power, particularly when attempting to detect genetic loci with very modest effects ^[5]. The ability to assemble sufficiently large cohorts remains a critical barrier, meaning that many true associations may not achieve genome-wide significance despite contributing to disease risk^[6]. For instance, the IBD5 haplotype, a confirmed Crohn’s disease (CD) risk factor, did not reach genome-wide significance in some studies, underscoring the challenge of detecting all relevant loci without exceptionally large sample sizes^[7].

Furthermore, the genomic coverage of genotyping arrays can be incomplete, particularly for rare variants or complex structural variations, which are often poorly represented by design ^[5]. This incomplete coverage reduces the power to detect rare, highly penetrant alleles, leading to a potential underestimation of their contribution to digestive system disease pathogenesis^[5]. Consequently, a failure to detect a significant association for a specific gene in a study does not definitively exclude its role, as it may be due to limitations in assay design or statistical power ^[7].

Phenotypic Heterogeneity and Generalizability

Current research often faces challenges in generalizing findings due to cohort biases and phenotypic heterogeneity. Many studies, including those exploring common genetic variations, have primarily focused on populations of European descent, necessitating further testing to confirm the validity of these genetic paradigms across other ancestries ^[7]. This limited population diversity can restrict the generalizability of identified associations and potentially overlook population-specific genetic risk factors or protective variants.

Moreover, the clinical presentation of digestive system diseases can vary significantly, especially between different age groups, complicating the interpretation of genetic associations. For example, pediatric-onset CD is more frequently associated with colonic involvement compared to adult-onset CD, and childhood-onset ulcerative colitis often presents with more extensive colitis and a stronger family history^[8]. Such phenotypic differences highlight the need for careful stratification and analysis to ensure that genetic findings are accurately linked to specific disease subtypes and to avoid confounding effects from heterogeneous patient cohorts.

Incomplete Genetic Architecture and Missing Heritability

Despite advances in identifying genetic variants associated with digestive system disease, these variants do not fully account for the entire genetic risk, pointing to a phenomenon known as “missing heritability”^[8]. A substantial portion of the genetic predisposition remains unexplained, indicating that many more genes or genetic mechanisms await discovery. This gap necessitates ongoing efforts to characterize additional genes and genetic pathways that contribute to inflammatory bowel disease (IBD) susceptibility^[8].

The modest individual contribution of common genetic variants to overall disease risk means that a comprehensive understanding requires identifying numerous additional variants, many of which may have even smaller effect sizes^[8]. This challenge underscores the continued need for extremely large sample sizes or the development of alternative strategies, such as focusing on individuals with early disease onset or utilizing complementary gene discovery approaches, to fully elucidate the complex genetic architecture of digestive system diseases^[5].

Variants

Genetic variations play a crucial role in influencing an individual’s susceptibility to a range of digestive system diseases by affecting fundamental cellular processes, metabolic pathways, and immune responses. This section explores several such variants and their associated genes, highlighting their implications for digestive health.

Variants within genes like ARHGAP15 (rs6717024 ), CARMIL1 (rs535816044 ), and RAB10 (rs193051903 ) are relevant due to their roles in maintaining cellular structure, intracellular transport, and immune function. ARHGAP15 helps regulate Rho GTPases, which are essential for cell shape, movement, and adhesion, processes critical for maintaining the integrity of the gut’s epithelial barrier and for proper immune cell activity; a variant here could compromise gut barrier function or alter inflammatory responses. CARMIL1 is involved in organizing the actin cytoskeleton, vital for cell motility and adhesion, meaning thatrs535816044 could impact the tight junctions between intestinal cells, potentially contributing to increased gut permeability and inflammation. RAB10, a small GTPase, regulates vesicle trafficking within cells, a process fundamental for nutrient absorption, mucus secretion, and antigen presentation by immune cells in the gut; a variant could disrupt these critical transport pathways, affecting overall digestive function and immune surveillance. Additionally,TAFA2 (rs535733797 ) encodes a chemokine-like protein, suggesting a role in immune cell communication and inflammation, which, if altered, could influence the immune landscape of the digestive tract.

Other variants impact metabolic regulation and gene expression, with direct consequences for digestive organs. The PNPLA3 gene, through its rs3747207 variant, is a well-established factor in lipid metabolism. This specific variant impairs the breakdown of triglycerides in the liver, leading to fat accumulation and significantly increasing the risk of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and progression to fibrosis and cirrhosis, which are major liver diseases. Similarly,ZNF708 (rs75446182 ) and PRDM4 (rs564110465 ) are involved in transcriptional regulation; ZNF708 is a zinc finger protein likely controlling the expression of other genes, while PRDM4 participates in chromatin remodeling and acts as a transcriptional repressor or activator. Variants in these genes can subtly alter the expression profiles of numerous downstream genes, impacting gut development, immune homeostasis, and cellular differentiation, thereby influencing susceptibility to various digestive conditions.

Finally, variants associated with pseudogenes or less characterized genes may still have indirect but significant implications. The variants rs540878969 , rs564110465 , and rs561844774 are located near or within pseudogenes such as IFITM8P, RN7SKP135, RPL17P38, PSME2P1, and KRT8P32. While pseudogenes are typically non-coding, some can exert regulatory functions, for instance, by modulating the expression of their functional gene counterparts. A variant in a pseudogene related to interferon-induced transmembrane proteins (like IFITM8P, influencing innate immunity) or keratins (like KRT8P32, crucial for gut epithelial structure) could indirectly affect immune responses or cell integrity in the digestive tract. Similarly, variants in genes likeCRTAC1 and R3HCC1L (rs576089196 ), though less directly linked to common digestive diseases, could influence broader cellular processes like extracellular matrix organization or nucleic acid binding, which are fundamental to the overall health and function of the digestive system.

Key Variants

RS ID	Gene	Related Traits
rs6717024	ARHGAP15	digestive system disease
rs535816044	CMAHP, CARMIL1	digestive system disease
rs75446182	ZNF708	digestive system disease
rs3747207	PNPLA3	platelet count serum alanine aminotransferase amount aspartate aminotransferase measurement triglyceride measurement non-alcoholic fatty liver disease
rs540878969	IFITM8P - RN7SKP135	digestive system disease
rs564110465	RPL17P38 - PRDM4	digestive system disease
rs576089196	CRTAC1 - R3HCC1L	digestive system disease
rs561844774	PSME2P1 - KRT8P32	digestive system disease
rs193051903	RAB10	digestive system disease
rs535733797	TAFA2	digestive system disease

Classification, Definition, and Terminology

Digestive system disease refers to a broad range of conditions affecting the gastrointestinal tract. Within the context of these studies, the primary focus is onInflammatory Bowel Disease (IBD) ^[1].

Definition of Inflammatory Bowel Disease (IBD)

IBD is characterized by chronic inflammation of the digestive tract ^[1]. The diagnosis of IBD requires specific criteria:

• One or more symptoms such as diarrhea, rectal bleeding, abdominal pain, fever, or complicated perianal disease^[9].
• These symptoms must occur on two or more occasions separated by at least eight weeks, or be ongoing for at least six weeks duration ^[9].
• Objective evidence of inflammation must be present, as determined by radiologic, endoscopic, and histologic evaluation ^[9].

Related Terms and Classifications

Inflammatory Bowel Disease (IBD) is a collective term for a group of inflammatory conditions. The main forms discussed in the research include:

• Crohn’s Disease (CD): A chronic inflammatory condition that can affect any part of the digestive tract, though it is frequently observed in the colon or ileum, or both locations ^[9]. CD can manifest in various forms:

  • Fistulizing form: Characterized by the development of abnormal connections (fistulas) ^[9].
  • Stenosing form: Involves the narrowing of the intestinal lumen (strictures) ^[9].
  • Inflammatory form: Primarily characterized by inflammation ^[9].
  • Ileal CD involvement: Specifically defined by mucosal ulceration, cobblestoning, stricturing, or bowel wall thickening, which can be identified through endoscopy reports, barium X-rays, operative reports, or pathology resection specimen reports. This definition is inclusive, covering individuals with “ileal only” involvement as well as “ileo-colonic” involvement ^[9].

• Ulcerative Colitis (UC): Another major type of IBD ^[10]. It is distinct from Crohn’s Disease^[9].

When diagnosing Crohn’s Disease, certain other conditions are specifically excluded to ensure an accurate classification:

• Acute infectious colitis ^[9].
• Indeterminate colitis ^[9].

Signs and Symptoms

Individuals with digestive system diseases, particularly inflammatory bowel disease (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC), can present with a variety of clinical signs and disease behaviors. The expression of CD may include fistulizing, stenosing, and inflammatory forms. Signs of CD can be observed in the colon, ileum, or both locations.

The diagnosis of CD is typically established through methods such as colonoscopy, barium radiological examination, and exploratory biopsy performed during abdominal surgery.

The phenotypes of CD and UC vary considerably among individuals, primarily concerning the sites of inflammation, the specific disease behavior, its severity, and the presence of extraintestinal manifestations. This variability is influenced by genetic factors. For instance, specific observations indicate that mutations in theCARD15 gene are a greater risk factor for ileal CD and stricturing behavior ^[11].

Causes of Digestive System Disease

Digestive system diseases, such as Inflammatory Bowel Disease (IBD), are complex conditions that arise from a combination of genetic predispositions and non-genetic factors. The enteric microflora is understood to play a central role in the development and persistence of these diseases.^[1]

Genetic Factors

Genetic factors contribute significantly to the risk of conditions like Inflammatory Bowel Disease (IBD) and Crohn’s Disease (CD), as indicated by studies of heritability in twins.^[12]Genome-wide association studies have identified several genetic variants and regions associated with Crohn’s disease. These include:

• A susceptibility variant in the ATG16L1 gene. ^[13]
• A locus on chromosome 5p13.1, near the PTGER4 gene, which may influence the expression level of the prostaglandin receptor EP4. ^[14]
• The IBD5 haplotype on chromosome 5q31. ^[15]

Environmental Factors

Beyond genetic predispositions, non-genetic elements also contribute to digestive system diseases. The enteric microflora is considered a key non-genetic factor, influencing the initiation and maintenance of disease.^[1]Research has also investigated the influence of lifestyle factors such as smoking on conditions like ulcerative colitis and Crohn’s disease.^[12]

Biological Background

Digestive system diseases encompass a range of conditions affecting the gastrointestinal tract. Among these, Inflammatory Bowel Disease (IBD) and Hirschsprung disease (HSCR) illustrate the complex interplay of genetic, environmental, and cellular factors that contribute to digestive health and disease.

Inflammatory Bowel Disease (IBD)

IBD, which includes Crohn’s disease (CD) and ulcerative colitis (UC), refers to chronic, relapsing inflammatory disorders of the gastrointestinal tract^[1]. These conditions typically manifest with a peak age of onset between the second and fourth decades of life ^[16].

Underlying Biology The prevailing hypothesis for IBD etiology suggests that common, beneficial intestinal bacteria trigger an inappropriate, overactive, and persistent immune response in the mucosal lining of genetically susceptible individuals ^[1]. This misguided immune reaction then leads to damage of intestinal tissues ^[1]. The enteric microflora, the community of microorganisms residing in the gut, is recognized as a crucial factor in both the initiation and ongoing progression of IBD^[13].

Genetic Factors Genetic predisposition plays a significant role in IBD pathogenesis. This is supported by several observations:

• Higher rates of IBD among Ashkenazi Jews ^[2].
• Tendency for IBD to run in families ^[2].
• Increased likelihood of both twins having IBD in identical (monozygotic) pairs compared to non-identical (dizygotic) pairs ^[2].

Research has identified specific genetic variants associated with IBD. For example, variations in the CARD15 gene and the IBD5haplotype have been linked to Crohn’s disease^[13]. However, these identified genetic factors explain only a small portion of the inherited risk for Crohn’s disease^[17]. More recently, a susceptibility variant for Crohn’s disease was identified in theATG16L1 gene ^[13]. Another novel susceptibility locus for Crohn’s disease on chromosome 5p13.1 is known to influence the expression levels of the prostaglandin receptor EP4^[14].

The clinical presentation of IBD, including the location of inflammation, disease behavior, severity, and manifestations outside the intestine, varies considerably among individuals^[13]. Studies suggest that the site and behavior of Crohn’s disease, such as inflammation in the ileum or stricturing (narrowing) of the bowel, are likely under genetic control, withCARD15 mutations being a greater risk factor for these specific phenotypes ^[13]. Like many complex conditions, IBD is understood to arise from a combination of genetic and non-genetic factors, where each individual factor may have a relatively modest impact on disease risk^[13].

Hirschsprung Disease (HSCR)

Hirschsprung disease is a congenital condition characterized by the absence of nerve cells (ganglion cells) in a segment of the bowel, leading to functional obstruction. The genetic complexity of HSCR can be understood by examining the molecular and cellular events involved in the development of the enteric nervous system (ENS)^[3].

Enteric Nervous System DevelopmentThe human gut forms from two primary layers: the endoderm, which gives rise to the mucosal lining, and the splanchnic mesenchyme, which differentiates into the muscle layers^[18]. Concurrently, neural crest cells (NCCs), originating from the vagal region of the neural tube, undergo a critical migration process. These NCCs proliferate and differentiate into the neurons and glia that coalesce to form the ganglion plexuses in the myenteric region, collectively known as the ENS ^[18]. During this intricate developmental process, NCCs must adapt to a constantly changing intestinal environment, which significantly influences their ultimate fate ^[18].

Genetic and Molecular Basis HSCR can result from severe mutations in a major gene that encodes a crucial molecule involved in ENS development ^[3]. The penetrance, or the likelihood of these mutations causing the disease, can be influenced by other genetic variations^[3]. Alternatively, HSCR may arise from the accumulation of multiple, less severe, and more common mutations in several genes that are part of the same signaling network ^[3]. Key molecular pathways involved in ENS development and maintenance include the neuregulin-I/ErbB signaling system ^[19]. Research indicates that the expression of ErbB2 in colonic epithelial cells is essential for the postnatal maintenance of the enteric nervous system ^[20].

Pathways and Mechanisms

Digestive system diseases involve a complex interplay of genetic factors, immune responses, and environmental triggers affecting the gastrointestinal tract. Research highlights distinct molecular and physiological mechanisms underlying conditions like Crohn’s disease and Hirschsprung disease.

Crohn’s Disease

The pathophysiology of Crohn’s disease (CD) often converges on mechanisms related to epithelial defense, the balance between innate and adaptive immune responses, and tissue repair or remodeling in response to inflammation and damage^[21]. Genetic susceptibility plays a significant role, with several genes and regions identified through genome-wide association studies.

• Immune Response and Bacterial Handling

  • NOD2/CARD15: This gene, also known as CARD15, is a major susceptibility factor for CD ^[11][22]. It is thought to be involved in the recognition of bacterial components and the modulation of innate immune responses.
  • ATG16L1: Variants in ATG16L1 are associated with an increased risk of CD ^[13]. This gene plays a role in autophagy, a cellular process critical for degrading and recycling cellular components, and is implicated in the cellular immune response to pathogens like Salmonella ^[13].
  • MST1: Macrophage stimulatory protein 1 (MST1) is involved in inflammation and the remodeling of tissue for wound healing processes ^[21].
  • APEH (APH): This gene encodes a serine peptidase that degrades bacterial peptide breakdown products in the gut, which may help prevent excessive immune responses^[21].
  • Certain genes contribute to stress fiber formation during the innate cellular immune response, particularly in the presence of effector proteins released by pathogenic Yersinia species ^[21].

• Epithelial Defense and Tissue Integrity

  • A susceptibility locus identified on chromosome 5p13.1, located in a gene desert, modulates the expression of the prostaglandin receptor EP4 ^[14]. Prostaglandins are important mediators of inflammation and mucosal protection.
  • The BSN gene, which encodes a scaffolding protein expressed in axons, is found within a centromeric region of a susceptibility locus ^[21]. Its precise role in CD mechanisms is under investigation.
  • The IBD5 locus has been associated with Crohn’s disease, with observed differences in its genomic localization and association across different ethnic groups^[15].

Hirschsprung Disease

Hirschsprung disease (HSCR) is characterized by the absence of ganglion cells in a segment of the colon, leading to functional obstruction. This condition arises from developmental disturbances of the enteric nervous system (ENS)^[18].

• Enteric Nervous System Development

  • HSCR is primarily a neurodevelopmental disorder of the gastrointestinal tract, involving the failure of neural crest cells to migrate, proliferate, or differentiate properly into the ENS^[18].
  • Familial and population risk for HSCR can be explained by segregation at multiple genetic loci ^[3].

• Neuregulin-I/ErbB Signaling System

  • The neuregulin-I/ErbB signaling system is crucial in both development and disease^[19]. Neuregulins are a family of growth factors that bind to ErbB receptor tyrosine kinases, influencing cell growth, differentiation, and survival ^[4].
  • Colonic epithelial expression of ErbB2, a receptor tyrosine kinase in the ErbB family, is essential for the postnatal maintenance of the enteric nervous system ^[20]. Disruptions in this pathway can contribute to the pathology of HSCR.

Clinical Relevance

Digestive system diseases, particularly inflammatory bowel disease (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC), carry significant clinical implications. Research indicates that the enteric microflora plays a central role in the initiation and maintenance of these conditions^[1]. IBD is understood to arise from a combination of genetic and non-genetic risk factors, with each individual factor contributing a relatively modest effect to the overall disease risk^[1].

Genetic studies have successfully identified specific variants associated with CD, including those in the CARD15 gene and the IBD5 haplotype ^[17]. While these findings contribute to understanding disease susceptibility, they currently explain only a small fraction of the heritability of CD^[17]. This highlights the ongoing need for further genome-wide association (GWA) studies to uncover additional genetic risk factors.

The clinical presentation of CD and UC varies considerably among individuals, encompassing differences in the sites of inflammation, disease behavior, severity, and extraintestinal manifestations. Genetic factors are believed to influence CD characteristics, with observations showing that CARD15 mutations are associated with a greater risk for ileal CD and stricturing behavior^[2]. This suggests a potential prognostic value for certain genetic markers in predicting specific disease patterns.

Despite advancements in identifying genetic associations, the variants discovered thus far account for only a small proportion of the overall familial aggregation of diseases like CD. Consequently, current genetic findings, whether considered individually or in combination, have limited utility in providing clinically useful predictions for disease progression or outcomes^[16]. This underscores the complexity of these conditions and the ongoing challenge in translating genetic insights into precise clinical prognostics for individual patients.

Frequently Asked Questions About Digestive System Disease

These questions address the most important and specific aspects of digestive system disease based on current genetic research.

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1. My family has gut issues; am I doomed to get them too?

Not necessarily, but you might have an increased risk. Digestive diseases like Crohn’s are complex, meaning both your genes and environmental factors play a role. While specific gene variants, like those in CARD15, can make you more susceptible, having these genes doesn’t guarantee you’ll develop the disease.

2. Can eating certain foods actually cause my digestive problems?

While food choices don’t directly cause diseases like IBD, environmental factors, including your diet and the bacteria in your gut (microflora), interact with your genetic makeup. This interplay can trigger or worsen digestive conditions in individuals who are genetically predisposed. So, certain foods might exacerbate symptoms for you.

3. Why do my gut issues feel so different from others with the same disease?

The way a digestive disease presents, like where inflammation occurs or how severe it is, can vary greatly from person to person, even with the same diagnosis. This is partly due to genetic factors; for example, specific changes in genes likeCARD15are linked to different types of Crohn’s disease, such as affecting the small intestine or causing strictures.

4. Does my ethnic background affect my risk for these gut diseases?

Yes, it can. Much of the research on genetic risk factors has focused on populations of European descent, and we know that genetic variations can differ between ethnic groups. This means your ancestry might predispose you to different risks or disease presentations, and more research is needed to understand these unique patterns globally.

5. Will my gut disease always be mild, or could it get really bad?

It’s hard to predict definitively, but genetic factors can influence how your disease progresses. For instance, some genetic variations, like certainCARD15mutations, are associated with a higher risk of more severe disease behaviors, such as the development of strictures in Crohn’s disease. Understanding your specific genetic profile could help predict your disease course.

6. Are my child’s digestive issues a different problem than mine?

Potentially, yes. Digestive diseases can present differently in children compared to adults. For example, pediatric-onset Crohn’s disease often involves the colon more extensively, and childhood-onset ulcerative colitis might show broader inflammation and a stronger family history, suggesting unique genetic influences at different ages.

7. Can my healthy habits overcome my family’s gut history?

Healthy habits are incredibly important and can significantly influence your risk and disease course, but they can’t completely “overcome” a strong genetic predisposition. Digestive diseases arise from a complex interaction between your genes and environmental factors. While you can manage the environmental side with good habits, your genetic susceptibility still contributes to your overall risk.

8. Could a DNA test tell me if I’ll get gut disease?

A DNA test can identify if you carry specific genetic variants, like those in CARD15 or IL23R, that are known to increase your susceptibility to conditions like Crohn’s disease. However, these diseases are complex, and many genes contribute with modest effects, so a test can indicate increased risk but not definitively predict if you will get the disease.

9. Why do doctors say my immune system affects my gut problems?

Your immune system plays a crucial role because many genes linked to digestive diseases, such as IL23R and ATG16L1, are involved in immune responses. These genes influence how your body handles inflammation and intracellular bacteria, which are key processes in the development of conditions like Crohn’s disease.

10. Does stress really mess with my digestion, or is it just me?

It’s not just you! While stress doesn’t directly cause digestive diseases, it’s a significant environmental factor that can interact with your genetic predispositions and affect your gut. Stress can influence your gut microflora and immune responses, potentially exacerbating symptoms or contributing to discomfort in individuals already susceptible to digestive issues.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[11] Hugot, J. P., et al. “A locus on chromosome 16q encodes a protein involved in innate immunity and is associated with Crohn’s disease.”Nature, vol. 411, no. 6840, 2001, pp. 599-603.

[12] Tysk, C., et al. “Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking.”Gut, vol. 29, 1988, pp. 990–6.

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[14] Libioulle, C., et al. “A novel susceptibility locus for Crohn’s disease identified by whole genome association maps to a gene desert on chromosome 5p13.1 and modulates the level of expression of the prostaglandin receptor EP4.”PLoS Genet, 2007.

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[18] Newgreen, D. F., and H. M. Young. “Enteric nervous system: development and developmental disturbances–Part 2.” Pediatric and Developmental Pathology, vol. 5, no. 4, 2002, pp. 329-349.

[19] Britsch, S. “The Neuregulin-I/ErbB Signaling System in Development and Disease.”Advances in Anatomy, Embryology and Cell Biology, vol. 190, 2007, pp. 1–65.

[20] Crone, S. A., et al. “Colonic Epithelial Expression of ErbB2 Is Required for Postnatal Maintenance of the Enteric Nervous System.” Neuron, vol. 37, 2003, pp. 29–40.

[21] van Heel, David A., et al. “A genome-wide association study of Crohn’s disease identifies a new susceptibility locus on chromosome 5p13.1 and confirms the NOD2/CARD15 and ATG16L1 loci.”Nature Genetics, vol. 39, no. 5, 2007, pp. 583-588.

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