Crohn's disease and genetics
Crohn's disease is a chronic inflammatory bowel disease that primarily affects the digestive tract, leading to symptoms such as diarrhea, abdominal cramps, rectal bleeding, and weight loss. It can impact any area from the mouth to the anus, although it commonly affects the ileum, the last part of the small intestine. The etiology of Crohn's disease is complex, involving a combination of genetic and environmental factors. Familial patterns suggest a genetic predisposition, particularly in individuals of Ashkenazi Jewish descent, with over thirty genes identified as potentially associated with the disease.
Among these, the NOD2 gene plays a crucial role by regulating the immune response to intestinal bacteria. Other significant genes include DLG5, TLR4, and IL23R, which are involved in maintaining intestinal health and immune function. While specific genetic factors may heighten the risk, the inheritance pattern is not straightforward, and environmental influences also contribute. There are no established guidelines for preventing Crohn's disease due to its unknown causes, but genetic counseling is advised for those with a family history of the condition. Treatment options vary from dietary adjustments and medications to surgical interventions in severe cases, highlighting the need for tailored approaches to management.
Crohn's disease and genetics
ALSO KNOWN AS: Crohn’s disease; CD; regional enteritis; regional ileitis
DEFINITION Crohn's disease is a severe, chronic inflammatory bowel disease. It causes inflammation, ulcers, and bleeding in the digestive tract. It usually affects the end portion of the small intestine called the ileum. However, any part of the digestive tract can be affected, from the mouth to the anus.
Risk Factors
Factors that increase an individual’s chance of getting Crohn's disease include having family members with inflammatory bowel disease and being of Jewish heritage.
Etiology and Genetics
Crohn's disease is a complex condition whose expression very likely involves many different environmental and genetic factors. A genetic component has been suspected for many years, since the disease has been known to run in families, and it is more common in people of Ashkenazi Jewish descent. By 2009, researchers had identified thirty-two different genes thought to be associated with Crohn's disease, and some suggested that this number could rise to one hundred or more. Because of the complexity of gene interaction and variable environmental factors, there is no clear predictability with regard to the inheritance pattern within families.
The single most important gene associated with an increased risk of developing Crohn's disease is called NOD2, found on the long arm of chromosome 16 at position 16q12. This gene specifies a protein known as nucleotide-binding oligomerization domain protein 2, and it functions as an intracellular receptor for bacterial products in white blood cells lining the intestinal epithelium. Disruption of this function is thought to alter the response to the bacteria naturally found in the intestines, causing the immune system to attack the intestinal epithelium and result in inflammation and possibly necrosis.
The DLG5 gene on the long arm of chromosome 10 (at position 10q23) encodes a scaffolding protein that helps maintain structural integrity of the intestinal epithelium, and mutations in this gene may result in a weakened scaffold that can increase disease susceptibility. On chromosome 9, the TLR4 gene (at position 9q32–q33) specifies a protein called toll-like receptor 4 that is involved with recognition of the lipopolysaccharide layer of bacterial cell walls, and disruption of this function could result in an altered immune response to the normal intestinal flora and subsequent inflammation. Other genes thought to have a significant impact on the predisposition to develop Crohn's disease include ITCH (at position 20q11.22), SLC22A4 (also known as OCTN1; at position 5q23.3) and IBD5 (at position 5q31–q33), IRGM (at position 5q33.1), ATG16L1 (at position 2q37.1), and IL23R (at position 1p31.2).
Symptoms
Symptoms include diarrhea, abdominal cramps and pain, rectal bleeding, anemia, weight loss, fatigue, weakness, nausea, fever, mouth sores, and sores and abscesses in the anal area.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history, and a physical exam will be done. Tests may include blood tests; a stool examination; barium swallow, a series of x-rays of structures inside the throat that are taken after drinking a barium-containing liquid; and a barium enema x-ray, the insertion of fluid into the rectum that makes the colon show up on an x-ray. Other tests include a flexible sigmoidoscopy, in which a thin, lighted tube is inserted into the rectum to examine the rectum and the lower colon; a colonoscopy, in which a thin, lighted tube is inserted through the rectum and into the colon to examine the lining of the colon; and biopsy, the removal of a sample of colon tissue for testing (may be performed as part of a flexible sigmoidoscopy or colonoscopy). If patients are diagnosed with Crohn's disease, their doctors will give them guidelines to follow.
Treatment and Therapy
Treatment may include avoiding foods that provoke symptoms. These foods are different for each individual and may include dairy foods (due to lactose intolerance), highly seasoned foods, and high-fiber foods.
Aminosalicylate medications are another treatment option and include sulfasalazine, mesalamine, and olsalazine. Anti-inflammatory medications used to treat Crohn's disease include prednisone, methylprednisolone, and budesonide. Other medications include immune modifiers, such as azathioprine, 6-mercaptopurine, and methotrexate; biologic therapy, including infliximab and adalimumab; and antibiotic medications, such as metronidazole, ampicillin, and ciprofloxacin.
Very severe Crohn's disease may not improve with medications. A patient may be advised to have the severely diseased section of his or her intestine removed; the two remaining healthier ends of the intestine are then joined together. The patient is still at high risk for recurrence of the disease elsewhere. Surgery may also be done if a patient has an obstruction or fistulas.
Untreated Crohn's disease may lead to fistulas, or abnormal connections between the intestine and other organs or tissues, such as the bladder, vagina, or skin. The untreated disease may also lead to intestinal obstruction, arthritis, eye inflammation, liver disease, kidney stones, gallstones, skin rashes, and osteoporosis.
Prevention and Outcomes
There are no guidelines for preventing Crohn's disease because the cause is unknown. At least two hundred genetic variations influence risk of Crohn's disease, but researchers say other factors such as environment also play a role. Experts recommend genetic counseling for individuals with a family history of the disease. Nearly half of patients undergo abdominal surgery in the ten years after diagnosis.
Bibliography
Carson-DeWitt, Rosalyn. "Crohn's Disease." Health Library. EBSCO, 6 Jan. 2014. Web. 18 July 2014.
Crohn's & Colitis Foundation of America. "What Is Crohn's Disease?" Crohn's & Colitis Foundation of America. CCFA, 2014. Web. 18 July 2014.
Garza-Hernandez, Debora, et al. "A Systematic Review and Functional Bioinformatics Analysis of Genes Associated with Crohn's Disease Identify More than 120 Related Genes." BMC Genomics, vol. 23, 2022, doi.org/10.1186/s12864-022-08491-y. Accessed 4 Sept. 2024.
Genetics Home Reference. "Crohn Disease." Genetics Home Reference. NIH/NLM, 14 July 2014. Web. 18 July 2014.
Goroll, Allan H., and Albert G. Mulley, Jr., eds. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 7th ed. Philadelphia: Wolters, 2013. Print.
MedlinePlus. "Crohn's Disease." MedlinePlus. NLM, 1 July 2014. Web. 18 July 2014.
National Digestive Diseases Information Clearinghouse (NDDIC). "Crohn's Disease." National Digestive Diseases Information Clearing House. NIDDK/NIH, 10 July 2013. Web. 18 July 2014.
National Human Genome Research Institute. "Learning about Crohn's Disease." Genome.gov. NHGRI, 27 Sept. 2011. Web. 18 July 2014.
Ranasinghe, Indika R., Chenlu Tian, and Ronald Hsu. "Crohn Disease." National Library of Medicine, 24 Feb. 2024, www.ncbi.nlm.nih.gov/books/NBK436021/. Accessed 4 Sept. 2204.
Sklar, Jill. Crohn’s Disease and Ulcerative Colitis: An Essential Guide for the Newly Diagnosed. 2d ed., rev. and updated. New York: Marlowe, 2007. Print.
Warner, Andrew S., and Amy E. Barto. One Hundred Questions and Answers About Crohn’s Disease and Ulcerative Colitis: A Lahey Clinic Guide. 2d ed. Sudbury: Jones, 2010. Digital file.