The Key Inflammatory Gene & Its Role in IBD (TNF)

What is TNF?

The TNF gene encodes a protein called tumor necrosis factor-alpha (TNF-alpha or cachexin), TNF-a plays a central role in the immune response and inflammation [R].

This cytokine, a type of cell signaling protein, is produced by different immune cells, including [R]:

• Macrophages
• Natural killer (NK) cells
• Neutrophils
• Mast cells

Variations in the TNF gene may cause improper production of TNF-alpha and contribute to a range of health conditions, such as autoimmune diseases, depression, and cancer [R, R, R].

Besides inducing inflammation and fever, TNF-a can suppress appetite and stimulate phagocytosis (“swallowing” damaged cells and pathogens) [R].

The TNF gene encodes TNF-alpha, a crucial inflammatory cytokine. Variants in this gene correlate with autoimmune conditions, depression, cancer, and more.

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 TNF-a in IBD Development

TNF-a is a crucial cytokine in IBD development. Increased expression and blood levels of this inflammatory protein are found in the majority of IBD patients [R, R].

TNF-a overproduction may open the door for gut autoimmunity and inflammation, especially Crohn’s disease. Scientists have developed anti-TNF antibodies with promising results in IBD treatment [R, R].

Before we dive into TNF variants associated with IBD, keep in mind that epidemiology and genetic factors of IBD can greatly differ between populations (e.g., Asians and Europeans). The effects observed in one population may not always translate to others [R, R].

Rs1800629

In a meta-analysis of 8,822 European participants, those with the “AA” genotype at rs1800629 had 84% higher UC and 69% higher CD rates [R].

This SNP has a similar association with UC but not with CD in Asians, according to a meta-analysis of over 45,000 subjects [R].

IBD Complications

Among 182 Portuguese subjects, rs1800629-A was associated with more severe IBD forms, gut perforations, and the need for surgery [R].

IBD patients with this variant were 4.5x more likely to develop colorectal cancer, according to a meta-analysis of 7 studies with 2,287 total participants [R].

Pediatric IBD

In a meta-analysis of 2,000 children, the rates of CD nearly doubled per each “A” allele. It was associated with both UC and CD in 547 Italian children. Those carrying the “A” allele also had severe CD forms and more surgical interventions [R, R].

In 162 Czech children, this SNP correlated with UC development. It didn’t impact CD rates, but children with the “A” allele had more severe disease forms [R].

Conflicting Results

Some studies in various ethnic groups failed to confirm the link between this SNP and IBD [R, R, R].

Two studies with European and Korean patients even reported the opposite results: lower “A” allele frequency among IBD patients [R, R].

The “A” allele at rs1800629 is associated with IBD development and severity in children and adults. Some conflicting results call for further investigation in large, well-designed trials.

Rs1799964

A meta-analysis of 6 studies and over 21,000 European descendants found a modest link between another TNF variant and IBD. People with rs1799964-C had 19% higher rates of Crohn’s disease [R].

The “CC” genotype was associated with Crohn’s in 208 children of French-Canadian origin [R].

On the other hand, two studies of 400 Iranian subjects showed no association or even the opposite effect of this SNP [R, R].

The “C” allele at rs1799964 may be associated with Crohn’s disease in European children and adults.

Rs1799724

In a study of two UK groups and over 2,000 total participants, the “CC” genotype at rs1799724 was associated with IBD, especially ulcerative colitis. A study of 535 Australian participants found a link between this genotype and Crohn’s disease [R, R].

Another Australian study (n=600) confirmed the association of the “C” allele with IBD [R].

How It Works

The “A” allele at rs1800629 can increase TNF-a expression 6-7 times, compared with the common “G” allele [R, R].

IBD patients carrying this allele often have worse gut inflammation and higher levels of TNF-a, CRP, and IL-1b [R, R].

People with the “CC” genotypes at rs1799964 and rs1799724 also had significantly higher TNF-a expression [R, R].

The above SNPs can increase TNF-a expression and thus contribute to gut inflammation.

SNP Summary and Table

Primary SNP:

TNF rs1800629

• ‘A’ = associated with higher rates and severity of IBD in children and adults
• ‘G’ = not associated with IBD

Population Frequency: Around 25% of European, 23% of African, and 12% of East Asian descendants carry at least one copy of the “A” allele. The “AA” genotype is much less common.

Other Important SNPs:

TNF  rs1799964

• ‘C’ = associated with higher rates of Crohn’s disease in children and adults 
• ‘T’ = not associated with IBD

Population Frequency: Around 34% of Europeans carry one and 4% carry both copies of the “C” allele. This allele is a bit less common in African populations.

TNF rs1799724

• ‘C’ = associated with higher IBD rates and Crohn’s severity
• ‘T’ = not associated with IBD

Population Frequency: Around 82% of European, 77% of East Asian, and 95% of African descendants carry the “CC” genotype.