Can Your Variants of This Gene Protect You From Inflammatory Bowel Disease? (TNFSF15)

The TNFSF15 gene encodes a cytokine from the tumor necrosis factor (TNF) family called ‘TNF superfamily member 15 (TNFSF15)’. The protein is also commonly known as TL1A (‘Tumor necrosis factor-like cytokine 1A’) and VEGI (‘Vascular endothelial growth inhibitor’) [R, R].

TNFSF15 is expressed at very low levels by tissue lining cells and inactive immune cells. Upon recognizing inflammatory cytokines, antibodies, and foreign microbes, immune cells such as T cells, macrophages, and dendritic cells increase their production of this protein [R, R, R, R].

TNFSF15 exerts its function by binding to DR3 (‘Death receptor 3’), a protein mainly produced by activated T cells, B cells, and natural killer cells [R, R, R, R].

By enhancing the effects of the cytokines that stimulate these processes, the TNFSF15/DR3 interaction promotes the proliferation, maturation, and function of the following immune cells:

• Th1 [R, R]
• Th2 [R, R]
• Th9 [R, R]
• Th17 [R, R]
• Tregs [R, R]
• NK cells [R, R]

As a result, TNFSF15 helps fight off infections by amplifying the immune response. Unfortunately, its excessive or uncontrolled activation is associated with inflammatory and autoimmune diseases such as IBD, rheumatoid arthritis, ankylosing spondylitis, and primary biliary cirrhosis [R, R].

What Is Inflammatory Bowel Disease?

Inflammatory bowel disease (IBD) is a group of autoimmune diseases characterized by inflammation and sores in the gut lining, which can result in diarrhea, abdominal pain, fatigue, fever, rectal bleeding, nutritional deficiencies, and weight loss [R].

Crohn’s disease and ulcerative colitis are the most frequently diagnosed subtypes of IBD. Both conditions share some features but differ in the regions affected:

• Crohn's may affect any portion of the gastrointestinal tract, but mostly the ileum (lower part of the small intestine). It involves ulcerations of all cell layers of the gut lining [R].
• Ulcerative colitis typically affects the colon and rectum. It causes the inflammation of the mucosal layer (innermost cell layer) of the gut [R].

The cause of IBD lies in a complex interplay of genetic and environmental factors [R].

Role of TNFSF15 in Gut Function and Inflammation

The TNFSF15/DR3 pathway promotes the development of T cells in the gut lining to produce inflammatory cytokines that help fight off bacterial and viral infections [R, R, R].

Importantly, the pathway activates a group of immune cells that promote mucosal immunity and barrier function (innate lymphoid cells) [R, R, R].

These studies support a role of TNFSF15 in sustaining gut lining function in normal conditions and during acute infections. However, its excessive activation seems to contribute to IBD and chronic gut inflammation.

IBD is associated with an increased production of both TNFSF15 and DR3. Higher levels of these proteins were measured in intestinal macrophages, dendritic cells, and T cells from people with Crohn’s disease, and in B cells from those with ulcerative colitis. In the case of Crohn’s, TNFSF15 levels were highest in the most severe cases [R, R, R, R, R].

Studies in mice show that TNFSF15 sustains bowel inflammation and tissue scarring by activating the Th1 and Th17 responses, resulting in an increased production of pro-inflammatory cytokines such as IL-13, IL-17A, and IFN-γ in the gut lining [R, R, R, R, R].

The TNFSF15 gene encodes a cytokine that amplifies the immune response. This normally helps fight off infections but can worsen IBD and other inflammatory conditions.

Protective Variants

Four TNFSF15 polymorphisms have been most widely studied:

• rs3810936: located in the region of the gene that encodes the protein (exon), it doesn’t change the sequence of amino acids but may modify its shape. Its major allele ‘C’ is associated with higher TNFSF15 levels and activity [R, R].
• rs6478108: its major variant ‘T’ is associated with increased TNFSF15 levels and activity in macrophages, colon cancer cells, and gut lining of people with IBD [R, R, R].
• rs6478109: located in the region that controls gene expression (promoter). Its minor variant ‘A’ has been associated with higher TNFSF15 levels in immune cells, but ‘G’ increased them in the gut lining of people with IBD and colon cancer cells [R, R, R, R].
• rs7848647: its minor variant ‘T’ was associated with lower blood TNFSF15 levels in people with rheumatoid arthritis, while ‘C’ increased the levels of this protein in the gut lining of people with IBD [R, R].

The minor variants at these polymorphisms protected from IBD (especially Crohn’s disease) in several studies of British, European, Japanese, Korean, Chinese, and Indian adults, as well as in Korean Children [R, R, R, R, R, R, R, R, R, R, R, R].

In contrast, the major ‘G’ allele of rs7848647 was associated with an early age of Crohn’s diagnosis (under 16 years old) in an American study [R]. 

The minor allele ‘A’ of rs4263839, associated with reduced protein levels in the blood and gut lining, protected against Crohn’s and ulcerative colitis in 3 studies on Indian, Chinese, and Italian populations. However, this variant was also associated with an increased progression of the disease in a Slovenian study [R, R, R, R]. 

The minor ‘C’ allele at rs7869487 was protective against Crohn’s disease in 3 studies on British, European, and Indian populations, and against both Crohn’s and ulcerative colitis in Japanese [R, R, R, R].

Inheriting several of the major variants together has been associated with higher levels of the TNFSF15 protein and more severe IBD symptoms in different populations [R, R, R, R].

Risk Variants

Two cases of minor TNFSF15 variants conferring increased susceptibility to Crohn’s disease have been identified:

• The ‘T’ variant of rs4979462 (in Japanese and Korean populations). It increases TNFSF15 expression by promoting the binding of a protein that activates it [R, R, R, R].
• The ‘T’ variant of rs6478106 (in Chinese and Japanese populations) [R, R].

Disease Outcomes

The protective variant at rs6478108 was, however, associated with Crohn’s complications such as narrowings and fistulas in a Korean study [R].

The minor variants of rs11554257 and rs2093403 were associated with increased severity of ulcerative colitis and need for the surgical removal of the colon [R].

TNFSF15 variants that lower the expression of the gene are associated with a reduced incidence of IBD, especially Crohn’s disease, while those that increase it confer susceptibility.

SNP Summary and Table

Primary SNP: TNFSF15 rs3810936

• ‘T’ = Reduced risk of Crohn’s disease and ulcerative colitis.
• ‘C’ = Normal risk of Crohn’s disease and ulcerative colitis.

Other Important SNPs: 

TNFSF15 rs6478108

• ‘C’ = Reduced risk of Crohn’s disease and ulcerative colitis.
• ‘T’ = Normal risk of Crohn’s disease and ulcerative colitis.

TNFSF15 rs6478109

• ‘A’ = Reduced risk of Crohn’s disease and ulcerative colitis.
• ‘G’ = Normal risk of Crohn’s disease and ulcerative colitis.

TNFSF15 rs7848647

• ‘T’ = Reduced risk of Crohn’s disease.
• ‘C’ = Normal risk of Crohn’s disease. Associated with early age of diagnosis.

TNFSF15 rs4263839

• ‘A’ = Reduced risk of Crohn’s disease and ulcerative colitis. Associated with disease progression and need for surgery.
• ‘G’ = Normal risk of Crohn’s disease and ulcerative colitis.

TNFSF15 rs7869487 

• ‘C’ = Reduced risk of Crohn’s disease and ulcerative colitis.
• ‘T’ = Normal risk of Crohn’s disease and ulcerative colitis.

TNFSF15 rs4979462 

• ‘C’ = Normal risk of Crohn’s disease.
• ‘T’ = Increased risk of Crohn’s disease.

TNFSF15 rs6478106 

• ‘C’ = Normal risk of Crohn’s disease.
• ‘T’ = Increased risk of Crohn’s disease.

Population Frequency

The distribution of all protective polymorphisms (rs3810936, rs6478108, rs6478109, rs7848647, rs4263839, and rs7869487) is very similar. Approximately 55% of the world population carries two copies of each major allele. The minor allele is most common in people with East Asian ancestry (~76% carriers of at least one copy) and especially rare in African descendants (only 1% carry two copies). 

The risk allele ‘T’ of rs4979462 is most common among people with an African background (~60% carriers of at least one copy) and rarest in European descendants (only 0.2% carry two copies).

The genotypes of the rs6478106 polymorphism are similarly distributed among the different ethnicities. Approximately 43% of the world population carries two copies of the major allele ‘C’ versus only 13% homozygous for ‘T’.