The Gene Involved in Gut Inflammation and IBD (IL23R)

What is IL23R?

The IL23R gene encodes one part of the receptor for interleukin 23, a pro-inflammatory cytokine [R].

IL-23 activates Th17 cells, enabling them to release cytokines such as IL-17, IL-21, and IL-22. The primary purpose of this mechanism, known as the IL-23/Th17 axis, is to combat pathogens such as fungi and bacteria and prevent them from entering the body [R, R, R].

Additionally, IL-23 plays a role in the formation of new blood vessels or angiogenesis [R].

IL23R encodes one part of the receptor for IL-23, a pro-inflammatory cytokine that protects against fungi and bacteria.

IBD

Crohn’s disease (CD) and ulcerative colitis (UC) are two of the most frequently diagnosed subtypes of inflammatory bowel disease (IBD). The cause of IBD lies in a complex interplay of genetic and environmental factors [R].

Crohn’s mostly affects the small intestine and involves ulcerations of all cell layers of the gut lining. Ulcerative colitis typically affects the colon and rectum, and involves the inflammation of the gut mucosal layer [R, R].

The Role of IL-23

Preclinical research has identified a crucial role of IL-23 in gut inflammation and different autoimmune conditions. Its activity peaks in the small intestine (terminal ileum) and colon, the most common IBD “targets” [R, R].

Animals with increased IL-23 expression have severe widespread inflammation, including the intestines [R].

Scientists have identified different SNPs in the IL23R gene associated with both Crohn’s disease and ulcerative colitis. Given their effects vary between populations, we will first outline the results for Europeans (Caucasians) and then mention the key differences in Asians.

A comprehensive review of 41 studies and over 47,000 participants has found a robust link between two SNPs and IBD [R]:

• rs11209026: the “A” allele was associated with lower rates of both CD and UC
• rs10889677: the “A” allele was associated with higher rates of both CD and UC

Combined, people with rs11209026-A had two times lower rates, and those with rs10889677-A had 37% higher rates of IBD.

In two meta-analyses of over 38,000 subjects, another IL23R variant correlated with ulcerative colitis. People with the “G” allele at rs7517847 had significantly lower UC rates. This allele was also protective against Crohn’s disease in a meta-analysis of 60 trials and 50K subjects [R, R, R].

When it comes to Asian populations [R, R, R, R]:

• rs11209026 is protective against CD but not against UC (non-existent in East Asia)
• rs10889677 is weakly associated with higher rates of UC but not CD
• rs7517847 is associated with neither CD nor UC

In European populations, people with rs11209026-A and rs7517847-G have lower chances, while those with rs10889677-A have higher chances of getting both Crohn’s disease and ulcerative colitis.

How It Works

Given the critical role of IL-23 in gut inflammation, it’s no wonder that IL23R variants correlate with IBD. According to researchers, these SNPs can change the structure of IL-23 receptors, making them more or less responsive to stimulation [R, R].

Over-stimulation of IL23R increases IL-17 and triggers gut inflammation. Both CD and UC patients have elevated IL-17 in the gut lining [R, R, R]

While overactive IL-23 is harmful, the lack of it may also impair the gut microbiome. The exact mechanism behind IL23R variants in IBD is likely more complex and has yet to be unraveled [R, R, R].

The above SNPs can change the structure of IL-23 receptors, making them more or less responsive to stimulation. Its over-stimulation can trigger gut inflammation and contribute to IBD.

SNP Summary

Primary SNPs:

IL23R rs11209026

• ‘G’ = not associated with Crohn’s disease or ulcerative colitis
• ‘A’ = associated with lower rates of Crohn’s disease and ulcerative colitis

Population Frequency: Around 12% of European descendants carry the “A” allele. This allele is nearly non-existent in African and East-Asian populations.

IL23R rs10889677

• ‘A’ = associated with higher rates of Crohn’s disease and ulcerative colitis 
• ‘C’ = not associated with Crohn’s disease or ulcerative colitis

Population Frequency: Around 50% of European descendants carry the “A” allele. It’s less common in East-Asian (46%) and African (24%) populations.

IL23R rs7517847

• ‘T’ = associated with higher rates of Crohn’s disease and ulcerative colitis
• ‘G’ = associated with lower rates of Crohn’s disease and ulcerative colitis 

Population Frequency: Around 65% of Europeans and East-Asians carry at least one copy of the “G” allele. It’s less common among African descendants (30%).