& Inflammatory Bowel Disease (IBD)

Genetics

KEY POINTS:

IBD runs in families. A person with IBD has a 30% or about 1 in 3 chance of having any relative with IBD.A person with IBD has a 10% or 1 in 10 chance of having a first degree relative with IBD. A first degree relative is a parent, child or sibling.
If a person has Crohn’s disease if they have a relative affected with IBD it is most likely that they will also have Crohn’s disease. However, they are more likely to have a relative with ulcerative colitis than a person in the general population. This suggests that the risk for developing Crohn’s disease and for developing ulcerative colitis is shared. It is possible that the risk lies in shared genes that predispose to these diseases. Alternatively, it is possible that the risk is something in the environment that triggers either form of IBD that family members share.
In pairs of identical twins if one twin has IBD there is a less than a 50% or 1 in2 chance that the other twin has IBD. This informs us that since identical twins share identical genes that there are other factors that may be more critical in determining whether a person develops IBD.
Every human has 46 chromosomes which are the vehicles that contain our genes.We get 23 chromosomes from each parent; so we inherit half of our genes from our mother and half from our father. Each gene makes a specific protein. If there is a mutation in a gene then it is possible the protein it is meant to produce may not turn out normally and therefore may not function normally. If for each gene, a human inherits 2 abnormal copies; 1 abnormal one from each parent then there is an even greater likelihood that the protein that gene makes will be abnormal.
There are over 200 gene mutations associated with IBD. This means that of the many thousands of genes that humans possess there are over 200 different genes that are mutated (different from normal) in some patients with IBD. It is not a guarantee that a person with IBD, either Crohn’s disease or ulcerative colitis will have a mutation in any of these 200+ identified gene mutations. Alternatively an individual with IBD may have 1 or several mutations in these identified genes.
As gene mutations are identified to be associated with IBD it is important to understand what proteins they make because that may provide clues to how IBD develops.

Is having one of the known gene mutations associated with IBD enough to cause IBD?

No. Many people in the general population have the gene mutations that have been associated with IBD and never get IBD. It may be that either a combination of gene mutations or a combination of a gene mutation and some environmental exposure may be necessary to cause IBD in an individual.

What type of gene mutations have been identified in IBD?

As gene mutations are identified to be associated with IBD it is important to understand what proteins they make because that may provide clues to how IBD develops.
The most well known gene mutation in IBD is called the NOD-2 mutation. NOD-2 is a protein on chromosome number 16 (every human gets 23 chromosomes from each parent.so everyone has 2 copies of every gene). Its function is to help the bowel mount a response against microbes that don’t belong. Having a mutation in this gene may mean that the person with the mutation may not defend normally against a harmful microbe. However, the human body is such that there are many checks and balances and a single gene abnormality of this type can be overcome by other genes that can do a similar job.
A mutation in NOD-2 gene is present in about 40% of persons with Crohn’s disease and about 15% of the healthy population. If one has a single mutation they are 3 times as likely to develop Crohn’s disease. If one has 2 mutations in the NOD-2 mutation they are 40 times as likely to develop Crohn’s disease.
Even with 2 NOD-2 mutations it is no guarantee that the person will develop Crohn’s disease. Further, many people, in fact the majority of people with Crohn’s disease do not have NOD-2 mutations.
Of the more common mutations associated with Crohn’s disease some involve the production of proteins like TNF which is known to be active in inflammation; or IL23 a protein also involved in inflammation, or ATG16 a protein that helps cells that need to be destroyed to get destroyed.
There are similar types of gene mutations that have been found in association with ulcerative colitis. There are some gene mutations that are present in both Crohn’s disease and ulcerative colitis.

Should people with IBD get genetic testing?

No. At present there is no reason to get testing of the types of genes one carries otherwise known as one’s genome. The main reason is that to date if it was found that someone with IBD carried one of these gene mutations associated with IBD it would not change their management.

Should people without IBD but who may be at risk of getting IBD because their parent or brother has it, get genetic testing?

No. At present there is no reason to get testing of the types of genes one carries otherwise known as one’s genome. The main reason is that to date if it was found that someone with IBD carried one of these gene mutations associated with IBD there is no current remedy to fix the gene mutation and there is not enough information available to advise such persons how they could avoid ultimately presenting with IBD. A simple way to think about this is why get information that you can not do anything about.

Is there any type of genetic testing that is useful in IBD?

One area of genetics that has an important role in IBD is pharmacogenetics. The term “pharmaco” refers to use of drugs. Pharmacogenetics refers to testing for certain genes that could predict how a person responds to taking certain drugs. For instance there is a genetic test that can determine how a person metabolizes the drug azathioprine, commonly used in the treatment of IBD. There is hope that many more gene tests will be developed to help us understand how different people metabolize or handle many of the drugs we currently use to treat IBD.

References

McGovern DP, Kugathasan S, Cho JH. Genetics of Inflammatory Bowel Diseases. Gastroenterology 2015;149(5):1163-1176.

Dixon LJ, Kabi A, Nickerson KP, McDonald C. Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis. Inflamm Bowel Dis. 2015;21(4):912-22.

Katsanos KH, Papadakis KA. Pharmacogenetics of inflammatory bowel disease. Pharmacogenomics 2014;15(16):2049-62.

Leone VA, Cham CM, Chang EB. Diet, gut microbes, and genetics in immune function: can we leverage our current knowledge to achieve better outcomes in inflammatory bowel diseases? Curr Opin Immunol 2014;31:16-23.

Last reviewed: March 2020

For more information and fact sheets about IBD and its treatment please visit: http://www.crohnsandcolitis.ca

Disclaimer: This information is provided for educational purposes only. Always consult a qualified health care professional for your specific care.

Source: This summary provides scientifically accurate information. It was prepared in a research review by researchers with the IBD Clinical and Research Centre, University of Manitoba with assistance from colleagues in Canada and internationally.

Acknowledgement: Preparation of this material was supported by funding from the Canadian Institutes of Health Research.

©2017 Charles N. Bernstein, John R. Walker on behalf of Manitoba IBD Clinical and Research Centre. This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License. You are free to copy and distribute this material in its entirety as long as it is not altered in any way (no derivative works).