Crucial Genetic Factor for Inflammatory Bowel Disease (IBD5)

Crohn’s disease and ulcerative colitis (UC) are the two most common subtypes of inflammatory bowel disease or IBD. In IBD, inflammation and sores in the gut lining can cause unpleasant digestive symptoms such as diarrhea, abdominal pain, fatigue, rectal bleeding, and more [R].

Besides well-known environmental triggers, IBD has a strong genetic component, and different gene variants have been associated with disease incidence and progression [R].

The Role of IBD5

Researchers have identified a group of genes on chromosome 5 that is strongly associated with IBD and named it IBD5. Besides NOD2 (CARD15), it’s the only genetic factor with a proven IBD link. The region contains different genes potentially involved in gut inflammation, including [R, R]:

• IRF1, which regulates interferons (signaling proteins)
• SLC22A4 and SLC22A5, which enable carnitine transport
• P4HA2, which allows collagen production
• C5ORF56 (unknown function)
• Genes for IL-4, IL-13 and other cytokines

During the past few decades, scientists have found various SNPs in this region associated with IBD incidence, and they have tried to discover the exact gene responsible for this link. The following chapter summarizes the main results.

IBD5 is a region of different genes strongly associated with IBD. Studies have found different variants in this region and tried to discover the ones that play a role in disease development.

A large meta-analysis gathered data from over 75,000 subjects to determine the critical IBD genetic factors. One SNP in the IBD5 region, rs2188962, correlated with 16% higher disease rates per “T” allele [R].

In another meta-analysis of over 15,000 participants, this variant was associated with 25% higher odds of Crohn’s disease [R]. A review including nearly 10,000 people didn’t find a significant link between rs2188962-T and ulcerative colitis [R].

The above variant belongs to a gene called C5ORF56. Scientists still don’t know the exact role of this gene and whether it plays a role in IBD development. Interestingly, the above study of Crohn’s disease patients found that all IBD5 variants were associated with decreased expression of another gene, SLC22A5, making it a candidate gene for IBD [R].

A study of 158 families with Crohn’s disease-affected members has also suggested SLC22A5 as a causal genetic factor. More precisely, the authors suggested two SNPs that may play a role in IBD development [R]:

• rs1050152-T in the SLC22A4 (OCTN1) gene
• rs2631367-C in the SLC22A5 (OCTN2) gene

These variants are almost always inherited together, along with other ones from the IBD5 region. As mentioned, SLC22 genes enable the uptake of the amino acid carnitine in the gut lining. 

A meta-analysis of 26 studies confirmed the link between the above two variants and IBD. They correlated with 20-23% higher rates of both Crohn’s disease and ulcerative colitis. This paper identified another significant IBD5 SNP, rs12521868, associated with 36% higher IBD rates [R].

The link between the IBD5 region and IBD development appears to be significant only in European descendants. Additionally, it may not play a role in ulcerative colitis in children [R].

Four IBD5 variants have shown a robust association with IBD in Caucasians. The SNPs likely involved in IBD development belong to the SLC22A4 and SLC22A5 genes, which enable the transport of carnitine in the gut.

How It Works

The SLC22A4 and SLC22A5 genes encode transport proteins (OCTN1 and OCTN2) that supply the gut lining with carnitine and other essential components. Mice lacking OCTN2 develop gut inflammation, ulcers, and perforations due to carnitine deficiency [R, R].

The gut barrier uses butyrate and other short-chain fatty acids as the primary source of energy and anti-inflammatory protection. Carnitine enables the uptake of fatty acids and their metabolism, making it an essential nutrient for gut health [R, R].

A study of 944 participants found that people with SLC22A4 and SLC22A5 variants have reduced gene expression in the blood and gut tissue, making them prone to inflammation. This confirms the mentioned link between IBD5 SNPs and lower SLC22A5 expression [R].

In reality, the situation is more complex because SLC22A5 expression can increase in response to gut inflammation [R]. Additionally, the science isn’t settled when it comes to the IBD5 region—other genes such as IRF1 and P4HA2 may also have functional roles [R, R].

People with IBD5 variants may have impaired carnitine transport in the gut, which depletes butyrate and paves the way for inflammation and gut damage.

SNP Summary

Primary SNPs:

SLC22A5 rs2188962

• ‘C’ = not associated with IBD
• ‘T’ = associated with higher odds of IBD, especially Crohn’s disease

SLC22A5 rs12521868

• ‘G’ = not associated with IBD 
• ‘T’ = associated with higher odds of IBD

SLC22A4 rs1050152

• ‘C’ = not associated with IBD 
• ‘T’ = associated with higher odds of IBD

SLC22A4 rs2631367

• ‘G’ = not associated with IBD 
• ‘C’ = associated with higher odds of IBD

Population Frequency

All SNPs in the IBD5 region are usually inherited together, which means they act as a single genetic factor. Around 63% of European descendants carry at least one copy of IBD-associated alleles. They are much less common in South Asian (16%) and African (4-7%) populations and nearly non-existent among East Asians.

There’s a notable exception for rs2631367 in African populations, where about 48% of people carry one copy and 19% carry both copies of the “C” allele.