Inflammatory Bowel Disease (IBD) is believed to result from an abnormal immune response to environmental triggers. But as the condition tends to run in families and certain ethnic groups, researchers are investigating potential genetic components and have found several associations.
Here’s where the research currently stands on the genetics of IBD, and what you can do to attenuate the risk.
Understanding Genetics & Heredity
Genetics is the study of how certain traits are passed down from parent to child as a result of changes in DNA sequences.
DNA (deoxyribonucleic acid) is a complex molecule within the nucleus of our cells. It carries essential instructions for our development, survival, and reproduction. This genetic information is stored within each cell in pairs of chromosomes – structures in which proteins wind up the DNA tightly enough to fit within the nucleus. We usually have 23 pairs of chromosomes in our cells, one of each pair from our mother and one from our father. A genome refers to the entire set of DNA instructions found in a cell.
Genetics often undergo alterations, which can lead to incorrectly formed proteins that can’t function properly and may impact the likelihood of developing a particular disease. Researchers can now identify certain genome alterations as risk factors for a range of diseases, including IBD.
IBD & Genetics: What’s the Connection?
More than 100 genes have been associated with a higher risk of developing IBD. The majority are related to immune function, in particular the interplay between the immune system and the microbiome (the bacterial environment in our body).
Researchers theorize that the genes which make an individual more susceptible to IBD are involved in the recognition and elimination of pathogenic bacteria. The altered expression of these genes and their influence on microbiota may be the cause of dysbiosis – an unbalance of gut bacteria found in IBD patients.
The strongest genetic risk for IBD, particularly Crohn’s disease, belongs to the NOD2 gene mutation. NOD2 encodes a protein that plays a vital role in maintaining microbiota homeostasis. The protein is expressed in our intestinal epithelial cells and white blood cells that are responsible for locating and eliminating harmful bacteria in the mucosal tissue. Mutations in NOD2 impact the body’s ability to target the harmful pathogens that may contribute to IBD development.
Another genetic alteration associated with Crohn’s disease is the ATG16L1 gene, which instructs and regulates the autophagy pathway. Autophagy is the body’s way of clearing out diseased cells, harmful proteins, and pathogenic bacteria. A loss of ATG16L1 function influences the ability of intestinal epithelial cells to secrete antimicrobial peptides, which promotes bacterial invasion in the intestine.
This process is implicated in various diseases, including IBD. Additionally, ATG16L1 and NOD2 appear to interact in the autophagy-dependent antimicrobial pathway, leading to intestinal dysbiosis, dysregulated immune responses, poor homeostasis, and a lack of antimicrobial protection.
Ulcerative Colitis Genetics
Although ulcerative colitis tends to run in families, researchers have discovered an association with somatic genetic mutations – meaning changes to our DNA that occur after conception and are not hereditary.
In UC, these somatic changes are largely related to IL-17, a strong pro-inflammatory signaling pathway associated with immune responses in the mucosa. Researchers recently found a higher frequency of IL-17-related gene mutations in the colon epithelium of UC patients than in healthy individuals, affecting the stability of many other pro-inflammatory cytokines.
IL-17-related gene mutations are now believed to increase the risk of UC.
Genetic Risk Factors in IBD
For both CD and UC, studies show that the more family members one has with IBD, the more likely one is to develop the condition, although Crohn’s disease shows a stronger familial pattern than UC.
Those with a first-degree relative with IBD have roughly 5-22% increased risk of developing the condition, while children whose parents both have IBD have a 1 in 3 risk of developing IBD by age 28.
Ethnicity & Environmental Factors in IBD
The occurrence of IBD varies among different ethnic groups and regions. Non-Hispanic white individuals have the highest incidence of IBD, with a risk three times higher than other populations.
Among specific ethnic groups, those of Ashkenazi Jewish descent are 2-4 times more likely to develop IBD compared to non-Jewish ethnic groups and Sephardic Jews. This increased risk may be linked to the presence of the NOD2/CARD15 mutation, which is more prevalent in Ashkenazi Jews and is associated with a higher risk of Crohn’s disease (CD) in white populations.
Environmental factors may also play a role, as American and European Jews have a higher IBD prevalence compared to Ashkenazi Jews living in Israel, where the Mediterranean diet is more common.
In the United States, African Americans have a lower prevalence of the NOD2 mutation, aligning with their lower incidence of IBD. While Canada has some of the highest rates of IBD globally, the rates among indigenous populations are significantly lower compared to Caucasian populations. Similar trends have also been observed among the Arab Bedouin population in Israel.
Why does any of this matter?
The research on different ethnic groups suggests that genetic changes, while not likely to cause IBD on their own, can make some individuals more susceptible if there is an interaction with certain environmental triggers.
Research on IBD and genetics is still ongoing, but it’s worth knowing if you and your family run a higher risk of development so you can get screened early, and avoid other contributing factors, such as a highly processed diet, smoking, or a sedentary lifestyle.