NOD2

The NOD2 gene provides instructions for making a protein called nucleotide-binding oligomerization domain containing 2. This protein is active in some types of immune system cells (such as monocytes, macrophages, and dendritic cells), which help protect the body against foreign invaders such as viruses and bacteria. The NOD2 protein is also active in several types of epithelial cells, including Paneth cells, which are found in the lining of the intestine. These cells play an important role in defending the intestinal wall against bacterial infection.

Many types of bacteria commonly live in the digestive system. Most of them are harmless, such as bacteria in the intestine that normally help digest food. Other bacteria, however, can infect the body and cause disease. The NOD2 protein is involved in recognizing certain bacteria in the intestine and stimulating the immune system to respond properly. When triggered by specific substances produced by bacteria, the NOD2 protein activates a protein complex called nuclear factor-kappa-B. This protein complex regulates the activity of multiple genes, including genes that control immune responses and inflammatory reactions. By activating nuclear factor-kappa-B, the NOD2 protein helps protect the digestive tract from bacterial invasion.

Crohn disease - increased risk from variations of the NOD2 gene

More than 30 variations in the NOD2 gene have been associated with an increased risk of Crohn disease in the lower part of the small intestine (the ileum). This increased risk has been found only in Caucasian (white) populations. The most common variation, written as 3020insC or 1007fs, leads to the production of a NOD2 protein that is slightly shorter than normal. Other common variations change single protein building blocks (amino acids) in the NOD2 protein. It is unclear how these genetic changes increase the risk of developing Crohn disease. Several studies have suggested that changes in the NOD2 gene prevent the protein from recognizing bacteria, allowing these microbes to grow unchecked and invade cells lining the intestine. An abnormal immune response to these bacteria may lead to chronic inflammation and the digestive problems characteristic of Crohn disease.

cancers - associated with the NOD2 gene

A few studies have suggested a possible association between changes in the NOD2 gene, particularly the common variation 3020insC, and the development of certain cancers. Although some of these studies found an increased risk of cancer in people with a NOD2 variation, other research found no such association.

other disorders - associated with the NOD2 gene

Mutations in the NOD2 gene have been identified in several families with a rare condition called Blau syndrome. This disorder is characterized by inflammation of the eye (uveitis), early-onset arthritis, unusual curvature of the fingers (camptodactyly), and a persistent skin rash. Researchers have found at least two NOD2 mutations in people with Blau syndrome. The identified mutations each change a single protein building block (amino acid) at position 334 in the NOD2 protein. At this position, the amino acid arginine is replaced with the amino acid glutamine (written as Arg334Gln or R334Q) or with the amino acid tryptophan (written as Arg334Trp or R334W). These mutations occur in a different region of the NOD2 gene than the genetic variations associated with an increased risk of Crohn disease.

Changes in the NOD2 gene also may be associated with early-onset sarcoidosis, a condition with signs and symptoms similar to Blau syndrome. Although NOD2 mutations have been found in a few families with early-onset sarcoidosis, researchers believe that these genetic changes are unlikely to be a major risk factor for this disorder.

Several studies have considered variations in the NOD2 gene as a possible risk factor for a condition called graft-versus-host disease (GVHD). Graft-versus-host disease can occur following certain cancer treatments, such as allogeneic stem cell transplantation. This procedure, which is typically used to treat cancers of the blood and immune system, replaces a patient's diseased blood-forming cells (a type of stem cell) with stem cells from a healthy donor. If the donor's stem cells (the graft) recognize the patient's body (the host) as foreign, they may attack organs and tissues such as the liver, digestive system, and skin. This potentially severe reaction is known as graft-versus-host disease. Researchers believe that variations in the NOD2 gene may influence the risk of developing severe complications of graft-versus-host disease following an allogeneic stem cell transplant. The presence of NOD2 variations in both the stem cell donor and the recipient is associated with the greatest risk of a severe reaction.