Can this Inflammatory Cytokine Cause Celiac Disease? (IL18R1, IL18RAP)

IL-18 is a cytokine whose main role is to activate inflammatory pathways that help fight off infections. Unfortunately, its improper regulation has been associated with allergies and inflammatory conditions [R, R, R].

The IL-18 receptor is a protein that activates different pathways in response to IL-18. This receptor comprises two parts, each one encoded by a different gene:

• The IL18R1 gene, short for ‘Interleukin 18 Receptor 1’ codes for the component that directly binds to IL-18 [R]. 
• The IL18RAP gene (‘Interleukin 18 Receptor Accessory Protein’) encodes the part of the receptor that transmits the IL-18 signal to its target proteins [R].

Both genes are located within a small region of the same chromosome. They are expressed in Th1 cells, B cells, and natural killer cells, and their production is stimulated in response to IFN-γ and IL-12 [R, R, R].

IL18 and Celiac Disease

Celiac disease is an immune disorder triggered in response to gluten, a protein found in grains such as wheat, barley, and rye. The immune cells recognize gluten as a threat and mount an aggressive inflammatory response that damages the small intestine and causes digestive issues and nutrient deficiencies due to poor absorption [R, R].

More specifically, the activation of CD4+ T cells by gluten causes their development into Th1 cells and the release of inflammatory cytokines such as IFN-γ and IL-21 [R, R, R, R].

Active IL-18 and both components of its receptor are produced in the intestinal lining of patients with celiac disease, but not of healthy people. IL-18 levels also drop when celiac patients go gluten-free, suggesting its involvement in the development of the disease [R, R]. 

IL-18 and other components of the same pathway may make the gut lining leaky to substances capable of causing intolerance, including gluten. Additionally, this cytokine seems to stimulate the development of Th1 cells and the release of IFN-γ in the gut [R, R].

IL18R1 and IL18RAP code for the two components of the IL-18 receptor. IL-18 activity is involved in the development and progression of celiac disease.

Two polymorphisms at the IL-18 receptor genes have been most widely studied: rs13015714 at IL18R1 and rs917997 at IL18RAP.

In a large study of almost 425,000 newborns from Europe and the US followed up for 15 years, the risk of eventually developing celiac disease was higher among carriers of the ‘G’ variant at rs13015714 [R].

In turn, the minor ‘T’ variant at the rs917997 polymorphism was first associated with celiac disease in a study of over 2,000 people from the UK. The study was extended by including almost 3,000 more samples from the Netherlands and Ireland, and the association was only replicated in the Dutch population [R].

Similarly, a Dutch study on almost 4,000 people associated this variant with celiac disease (but not with rheumatoid arthritis) [R].

Although some studies from Spain and Italy found little or no association between the ‘T’ variant and celiac disease, a meta-analysis concluded that the allele is linked to this condition at least in some European populations [R, R, R, R].

A few studies have investigated both polymorphisms simultaneously.

For instance, a study on over 3,000 people associated the minor variants at both rs13015714 and rs917997 with celiac disease in a Hungarian population and, more weakly, in Finnish and Italians. The association was strongest if both variants were inherited together [R].

A Spanish study on over 1,500 people also associated both variants with celiac disease [R].

However, a Swedish-Norwegian study on 325 families with celiac disease couldn’t link any of these variants to the condition [R].

Interestingly, these polymorphisms have also been associated with other digestive conditions such as IBD and esophageal and stomach cancer [R, R, R, R].

How May These Variants Interact with Celiac Disease?

The rs13015714 polymorphism of IL18R1 is located in a region of the gene that is removed during the process of producing the protein (an intron). Little is known about the effects of its minor ‘G’ variant on IL18R1 activity and one study found that it didn’t modify the expression of the gene [R].

In the case of IL18RAP, the minor ‘T’ variant of rs917997 is associated with a reduced expression of the gene and the production of not only the conventional form of the protein but also an alternative version [R].

Due to its more evident effect on the activity of the gene, some scientists believe that rs917997 plays the main role in celiac disease. Interestingly, a study found that the minor variant of rs917997 also reduces the expression of other genes located within the same region, including IL18R1 [R].

Nevertheless, it seems counterintuitive that a polymorphism presumably impairing IL-18 signaling worsens an autoimmune condition such as celiac disease. Some preliminary, yet unproven attempts to explain the potential mechanisms of this variant include:

• The alternative version of the IL18RAP protein could interact with other proteins and contribute to the onset and worsening of celiac disease through them [R].
• The biology of celiac disease is not fully understood and some mutations reducing the inflammatory response could worsen this condition, as has been shown for Crohn’s disease [R].
• Reduced IL-18 activity could shift the composition of the gut microbiota to one that contributes to the disease [R].

One variant of IL18R1 and one of IL18RAP have been associated with celiac disease in several European populations. Further research is needed to determine how they contribute to this condition.

SNP Summary and Table

Primary SNP: IL18RAP rs917997

• ‘C’ = Not associated with celiac disease.
• ‘T’ = Increased risk of celiac disease.

Other Important SNPs: 

IL18R1 rs13015714

• ‘T’ = Not associated wtih celiac disease.
• ‘G’ = Increased risk of celiac disease.

Population Frequency

The ‘C’ allele of rs917997 and the ‘T’ allele of rs13015714 are the most common ones and approximately 87% of the world population carries at least one copy in each case. The genotype distributions are very similar in the global population and in people of European ancestry.

While the minor alleles at both polymorphisms are even less common in African descendants, they are not so rare in people with American and Asian backgrounds.