Crohn’s disease is complex, chronic disorder primarily affecting the digestive system and with no single known cause. What we do know, though, is that this disease occurs more often in people with northern European ancestry and of eastern and central European (Ashkenazi) Jewish descent. When epidemiologists (who study disease development) identify this type of pattern for a disease, it gives them a clue that suggests genetics are at play.
Add to that the fact that if one identical twin has Crohn’s disease, there is a 58.3% chance the other has it too, while the rate of concordance is just 3.9% for non-identical twins, and you have yourself a pretty solid case suggesting the involvement of genes. (R)
It’s no big surprise, then, that in recent years, scientists have uncovered hundreds of genetic locations and at least 10 genes significantly involved in Crohn’s disease. Before we get to those, let’s look at the symptoms of Crohn’s disease and whom it affects.
What is Crohn’s disease?
Crohn’s disease is a form of inflammatory bowel disease (IBD) and is characterized by an abnormal immune system response that leads to excessive inflammation in the digestive tract. Typically, this occurs in the intestinal walls, especially in the ileum (the lower part of the small intestine), but it can also affect tissue anywhere from the mouth to the anus. Ulcerative colitis is another form of IBD, but, unlike in Crohn’s disease, ulcerative colitis is typically isolated to the colon.
Crohn’s disease can arise at any age, but usually appears when a person is an older teenager or in their 20s. And, because inflammation waxes and wanes according to a whole heap of factors, symptoms of Crohn’s disease tend to flare up throughout life, and especially at times of stress.
As tissues become inflamed and ulcers develop in the digestive tract, symptoms such as abdominal pain, cramping, weight loss, fever, loss of appetite, and persistent diarrhea can occur. Bleeding may also lead to discolored stools and anemia, if blood loss is persistent and/or severe.
Some people with Crohn’s disease also experience symptoms related to inflammation in other parts of the body, such as in the joints, skin, and eyes. Scar tissue and inflammation can also cause intestinal blockages, and ulceration can lead to the development of fistulae, bridge-like connections between areas of tissue such as the intestine, skin, bladder, or vagina.
Crohn’s disease and genetics
If you have Crohn’s disease, chances are that it also affects other people in your family. About 15% of people with Crohn’s disease have a parent or sibling who also has Crohn’s. And, as mentioned, if you have an identical twin with the disease, you have a 58.3% chance of also having Crohn’s disease. (R)
At least 200 genetic variations have been identified that affect your risk of developing Crohn’s disease. These appear to modulate risk via the immune system, and through changes to the bacterial balance in the intestines.
Some of the genes identified so far that have been associated with an increased risk of developing Crohn’s disease include:
Many of these genes are located on chromosomes 5 and 10. Mutations in four genes (ATG16L1, IL23R, IRGM, and NOD2) have gained the most attention, with variants in NOD2 (on chromosome 16) the first to be linked to an increased risk of developing Crohn’s disease. Around 30-50% of people in the western hemisphere carry a disease-causing mutation in at least one allele of NOD2, and people who have two mutated alleles have a 20- to 40-fold increased risk of developing Crohn’s disease. (R)(R)
Data from 51 studies involving over 28,000 people, including more than 12,000 with Crohn’s disease, revealed that people with the ATG16L1 variant rs2241880 had a 38% increased risk of Crohn’s disease. The ATG16L1 mutation also has been associated with an increased risk of necrotizing enterocolitis in premature infants. (R)
In contrast, people with the IL23R variant rs11209026 were 54% less likely to develop Crohn’s disease. (R) Other research has also found that the rs1343151 and/or rs7517847 variants strongly reduce the risk of developing Crohn’s disease. People carrying the A allele of rs1343151, meanwhile, have a significantly decreased risk of developing the condition in childhood, while those carrying the G allele in rs7517847 are less likely to develop Crohn’s disease when aged 17-40. People with the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, are also less likely to require a bowel resection if they do develop the disease. (R) IL23R appears to be an especially rich target for nutrigenomic intervention in Crohn’s disease; more on this below.
Many of the genes just mentioned appear to modulate the risk of Crohn’s disease via immune system pathways. This is because they affect the production of proteins that play a role in a process called autophagy, which is where immune system cells engulf and destroy bacteria, viruses, and other invading organisms. As such, genetic mutations affect the intestinal immune system’s normal response to bacteria. This can mean that the immune system fails to destroy bacteria, leading to infection, and can also result in an excessive response that causes the body to damage its own cells. Combined with dietary, environmental, and lifestyle factors, such genetic variations may increase the risk of inflammation and ulceration in the digestive tract. (R)
Other genes implicated in Crohn’s disease include vitamin C transporter genes and those affecting selenium transport. For instance, the single nucleotide polymorphism (SNP) rs10063949-G allele in the SLC23A1 gene has been associated with an increased risk of Crohn’s disease, with a 2.5-fold increased risk of the disease in people with the rs10063949-A/G variation and a 4.7-fold risk for people with the rs10063949-G/G variation compared to wild-type homozygotes. (R)
Crohn’s disease genes for susceptibility vs. progression
For many years, scientists thought that to develop Crohn’s disease a person needed a critical mass of mutations in different genes. Rather than one single genetic mutation causing the disease, it was believed that there was a “tipping point” at which cumulative variations created the conditions for the disease. In recent years, however, research has shown that not all the genetic mutations associated with Crohn’s disease increase the risk of the disease developing. Instead, some genetic variants seem to affect disease progression, but not its development. (R)
This discovery is important because by the time someone is symptomatic with Crohn’s disease, there’s no point trying to modulate the expression of the genes responsible for the development of the disease. Instead, it seems smart to focus on finding ways to modulate the expression of genes involved in disease progression and symptom severity.
In a groundbreaking study, researchers found that of the 170 loci involved in disease susceptibility, not one was associated with disease progression or prognosis. (R) And, conversely, at least four genetic variants have been discovered that don’t appear to influence how likely you are to develop Crohn’s disease, but do affect disease progression:
FOXO3 is involved in the release of tumor necrosis factor alpha, a cytokine (protein) that forms part of the immune system’s response to infection. In the case of Crohn’s disease, the FOXO3-TNF-alpha relationship appears to prompt the immune system to attack the body itself, with this gene also involved in the autoimmune disease rheumatoid arthritis.
IGFBP1 also affects the immune system and is linked to rheumatoid arthritis, as is the genetic variant in the MHC region. However, some genetic variants in the MHC region seem to affect the risk of Crohn’s disease while others affect its prognosis and symptom severity.
The XACT gene is active in the intestines, but little is currently known about how it affects Crohn’s disease.
Crohn’s disease and other health issues
Considering just how many genes are involved in Crohn’s disease, it’s understandable that there is some overlap with other health issues. A genetic link has been found between Crohn’s disease and diabetes, as well as rheumatoid arthritis and psoriasis. Crohn’s disease also seems to be linked to Ankylosing Spondylitis, with the two disorders sharing at least seven genes, four of which involve immune function. (R)
Risk factors for Crohn’s disease
Lifestyle, diet, environment, and genetics seem to be co-conspirators when it comes to Crohn’s disease. Smoking, for instance, doubles the likelihood of developing Crohn’s and increases the frequency and severity of flare-ups. (R) People who live in urban areas have also been found to be 42% more likely to have Crohn’s disease, which suggests that factors such as pollution, sedentary lifestyles, and diet might play a role in the disease. (R)
Indeed, diets high in animal fat and low in fruits and vegetables are most strongly associated with an increased risk of IBD. (R) It makes sense that a diet high in sugars and saturated fats (especially pro-inflammatory animal fats) and lacking in antioxidants and other vital nutrients, could contribute to Crohn’s disease by promoting intestinal inflammation, altering the gut microbiome, and impairing healing and immune function. (R)
Fiber is a contentious issue for people with IBD, given that some types of fiber can exacerbate symptoms while others may help reduce inflammation. Diets high in soluble fiber, for instance, can help lessen inflammation because they increase production of the anti-inflammatory short-chain fatty acid butyrate in the intestine. (R) Diets high in FODMAPs may, however, exacerbate symptoms in some people, with a low-fiber diet often advised during flares of IBD.
FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols) are types of fiber that are poorly absorbed in the gut, which can lead to excess gas production, bloating, abdominal pains, cramps, diarrhea, and constipation. Many people with Crohn’s disease, as well as irritable bowel syndrome, have success with a low-FODMAP diet, although this should be done under the guidance of a qualified nutritionist as cutting out a wide range of foods puts you at risk of nutrient deficiencies.
Crohn’s disease itself presents an increased risk of nutrient deficiencies, likely through malabsorption and increased demand for certain nutrients to facilitate healing. Nutrients that are particularly problematic include iron, calcium, zinc, magnesium, vitamin D, vitamin B12, folic acid, and vitamin A. (R)
Nutrigenomics and Crohn’s disease
Crohn’s disease, and IBD in general, is one of those areas of nutrigenomics where things get even more complex than usual. That’s because there are more than 3 million unique genes within the gut, courtesy of the microbiome and sometimes referred to as our second genome. (R) These genes vastly outnumber your own genes and, thanks partly to the transient nature of some gut bacteria, create a somewhat moving target for epigenetics and nutrigenomic interventions.
One target that has been identified is adherent invasive Escherichia coli (AIEC), a pathogen found in a staggering number of people with Crohn’s disease. In one study, AIEC was isolated from 36% of ileal lesions in people undergoing surgery for Crohn’s disease, compared to just 6% of healthy controls. (R) Taking steps to control or eradicate AIEC may be useful in Crohn’s disease, therefore, with studies showing that the probiotic E. coli Nissle 1917 (EcN) may do just that. (R)
Early on in this article, we mentioned how Crohn’s disease disproportionately affects people with specific ethnic backgrounds. While where you live might not seem, at first glance, to fundamentally alter your immune function, the truth is that a person’s microbiome is greatly dependent on their geographic location and diet. In one study, researchers found that African children had a gut microbiome rich in Bacteroidetes species but poor in Firmicutes and Enterobacteriaceae. The guts of European children were completely opposite however, with ramifications for how each population would digest food and interact with intestinal pathogens, as well as how genes would be expressed in the gut. (R)
What’s more, the increased prevalence and spread of IBD coincides with decreased biodiversity in the gut microbiome, in large part due to a western-style diet. (R) While association isn’t causation, it seems likely that environment, diet, your microbiome, and genetic factors interact in complex ways to alter a person’s risk of Crohn’s disease and to affect how the disease progresses. (R)
Fighting Crohn’s disease with diet
As we noted earlier, certain variants in the gene IL23R are associated with a decreased risk of Crohn’s disease. As such, researchers are looking at strategies to reduce the expression of IL23R in people with Crohn’s disease to help reduce disease progression. By down-regulating the activity of the gene, nutrigenomic interventions may help reduce the production of cytokines such as interleukin-17 (IL-17) and TNF-alpha that are implicated in IBD. Several bioactive nutrients have been found to interact with this gene, including caffeic acid phenethyl ester (CAPE), epigallocatechin gallate (EGCG), docosahexaenoic acid (DHA), and linoleic acid (LA). Indeed, EGCG (found in green tea) and DHA (found in fish and algal oil) significantly inhibited both inteluekin-17 and TNF-alpha expression in one study. (R)
In conclusion, while research is ongoing into the relationship between Crohn’s disease and genetics, sufficient evidence exists to support the idea that dietary measures could influence the expression and impact of genes (whether yours or those of your second genome) involved in the condition. For some people, green tea and DHA may help. In general, though, the smart move seems to be to eat a predominantly plant-based diet that is low in animal fats and sugar, and high in fiber, prebiotic, and probiotic foods. (R)
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