Alaa Muhsen Rejoub

“173708”

The role of CDH1 gene in Peptic Ulcer

Peptic ulcer disease (PUD) is typically identified as a mucosal lesion in the stomach or duodenum, mucosal

break greater than 5 mm to several cm in size and having visible depth(1). The etiology of PUD is

multifactorial, both genetic and environmental factors play crucial roles in its development(2). One of the key

players in this process is the Helicobacter pylori infection(3). This paper will explore the fundamental biology

of PUD, identify susceptibility genes such as CDH1(Epithelial-cadherin which encodes E-cadherin), review the

epidemiology of the disease and discuss environmental factors including diet and lifestyle that contribute to the

disease.

The stomach and duodenum mucosal lining are normally protected by a layer of mucus that serves as a

barrier against the damaging effects of gastric acid. The pathophysiology of peptic ulcers involves an imbalance

between mucosal protective mechanisms (mucin, bicarbonate and prostaglandins) and harmful factors (gastric

acid and pepsin) in the gastrointestinal (GI) lining(4). When this imbalance occurs, varying degrees of gastritis

or duodenal ulcer will form causing symptoms such as pain, bleeding and potentially severe complications like

perforation or gastric obstruction(5).

Several genes have been implicated in the pathogenesis of PU by influencing the severity of inflammation

caused by H. pylori which is a major cause of peptic ulcers. Most notably those involved in the integrity of the

gastric mucosa calcitonin gene-related peptide (CGRP), immune responses (IL-1β, TNFα, TLR4 and CD14),

Human Leukocyte Antigen (HLA) and CYP2C19 genes(6-9). Variations in these genes can lead to increased

gastric acid production and metabolism of proton pump inhibitors, so increasing the risk of ulcer formation.
 The CDH1 gene located on chromosome 16q22.1, is a tumor suppressor gene that encodes the protein E-

cadherin. This protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance

of cell-cell adhesion and maintaining the integrity of epithelial tissue. The CDH1 gene is most associated with

hereditary diffuse gastric cancer (HDGC)(10). The plasma level of CDH1 may serve as a risk marker against

gastric cancer. H. pylori can disrupt E-cadherin-mediated cell adhesion by producing bacterial proteases that

cleave E-cadherin. This disruption weakens the epithelial barrier leading to inflammation and the formation of

peptic ulcers.

PUD has been a longstanding public health concern with an estimated prevalence of 10% of the global

population(11). The disease is more common in adults, particularly in those between the ages of 30 and 50 and

for duodenal ulcers and those over 60 years for gastric ulcers, it is associated with a higher incidence in men

than women(12). Epidemiological studies have shown that PUD is closely linked to H. pylori infection which is

found in more than half of the world’s population. However, only a subset of infected individuals will develop

ulcers, suggesting the involvement of genetic susceptibility factors(13).

Familial clustering of PUD has been observed, supporting the role of genetic factors in disease susceptibility.

For example, studies have found a higher incidence of PUD among individuals with a family history of the

disease(14, 15). Additionally, the discovery of genetic mutations such as those in the CDH1 gene has furthered

the understanding of genetic contributions to the development of PUD. Research has also shown that

individuals with genetic mutations in CDH1 may be at increased risk of both gastric cancer and PUD,

highlighting the genetic link between these diseases(16, 17).

 Genetic testing for individuals with recurrent peptic ulcers, particularly those with a family history of gastric

cancer or diffuse gastric cancer may warrant investigation for CDH1 mutations. Understanding these genetic

factors is crucial for developing personalized treatment and targeted prevention strategies.

In addition to genetic factors, environmental factors play a significant role in the development of PUD. The

most well-established environmental risk factor is H. pylori infection. H. pylori is a Gram-negative bacterium

that colonizes the stomach lining and induces chronic inflammation(12), leading to the development of ulcers. It

is estimated that H. pylori infection is responsible for approximately 70-90% of duodenal ulcers and 60-80% of

gastric ulcers(18).

H. pylori contribute to ulcer formation through multiple mechanisms. The bacteria produce urease, which

neutralizes stomach acid, allowing the bacteria to survive in the acidic environment of the stomach. H. pylori

also produce virulence factors, such as CagA and VacA, which interfere with the host’s immune response and

promote tissue damage(19). In individuals with genetic susceptibility such as those with mutations in the CDH1

gene, H. pylori infection can exacerbate epithelial disruption, leading to ulcer formation.

Dietary factors also influence the risk of developing PUD. High intake of alcohol, caffeine, and spicy foods

has been associated with an increased risk of ulcer formation, although the direct causal relationship remains

unclear. Smoking is another significant environmental factor as it increases gastric acid secretion and impairs

mucosal healing, making the stomach more vulnerable to ulceration(20).

 Certain medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA)

that inhibit cyclooxygenase (COX) enzymes, which are essential for prostaglandin synthesis. Prostaglandins are

essential for maintaining the gastric mucosal barrier and promoting healing, using this medication leading to

damage to the stomach lining and increasing the risk of ulcers(21).

The combination of heavy workloads, long working hours, workplace stress, and rotating night shifts creates a

multifaceted risk environment for peptic ulcers. These factors work together to increase acid secretion, disrupt

protective mechanisms, impair healing, and foster behaviors that exacerbate the condition. The physiological

effects of stress combined with lifestyle disruptions make individuals in high-stress jobs or those with irregular

work schedules more susceptible to peptic ulcer disease(22).

Excess stomach acid or hyperacidity is a significant factor in the development of peptic ulcers, as it can

overwhelm the protective mechanisms of the stomach lining leading to mucosal damage. One notable condition

associated with hyperacidity is Zollinger-Ellison syndrome, which is a rare disorder characterized by the

presence of gastrin-secreting tumors (gastrinomas). These tumors stimulate excessive production of gastric acid,

significantly increasing the risk of ulcer formation(23).

Conclusion

PUD is a complex condition influenced by both genetic and environmental factors. Genetic mutations in

susceptibility genes like CDH1 contribute to the development of ulcers by weakening the integrity of the

epithelial barrier in the stomach lining. Environmental factors, particularly H. pylori infection play a central role

in the pathogenesis of PUD by inducing chronic inflammation and facilitating ulcer formation. Understanding

the interplay between genetic predisposition and environmental influences is essential for developing

personalized treatment and prevention strategies for PUD.

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