Could This Gene Play A Role In Inflammatory Bowel Disease? (STAT3)

The STAT3 gene codes for one member of a family of proteins called signal transducer and activator of transcription, or just “STAT” for short. STAT proteins are activated by other proteins (such as JAK), which causes them to bind to DNA in order to turn certain genes “on” or “off” [R].

When it comes to the STAT3 protein specifically, its main role is to control the expression of genes involved in the growth, development, and activation of immune system cells. This process is triggered by “messenger molecules” called cytokines. While STAT3 responds to many different cytokines, the main ones include IL-6, IL-10, IL-11, IL-15, and IL-22 [R, R, R, R].

The STAT3 gene encodes a protein that either activates or blocks the expression of genes required for the function of immune cells, depending on how the protein is activated.

STAT3 and Immunity Regulation

The immune system protects us from infections and cancer under normal circumstances, but can also cause allergies and inflammatory/autoimmune disorders when imbalanced! STAT3 responds to cytokines that either activate or block the immune response — in other words, it is one of the mechanisms your body uses to fine-tune the immune system.

On the one hand, STAT3 contributes to the development and function of the cells that:

• Promote inflammation and kill microbes (neutrophils) [R, R]
• Present infectious particles to T-cells (dendritic cells) [R]
• Produce antibodies (B-cells) [R, R, R]
• Fight off infections, but which may cause autoimmune and inflammatory disorders if overactivated (Th17) [R, R, R]
• Quickly respond to repeated infections that the body has already developed immunity against (memory T-cells) [R, R]

STAT3 also blocks the immune response by reducing the production of immunosuppressive T-cells (also known as “Tregs”) [R].

On the other hand, STAT3 can also act as an immunosuppressant by:

• Increasing the expression of its own blocker (SOC3) [R, R, R]
• Preventing the development of dendritic cells [R]
• Blocking the production of pro-inflammatory cytokines by white blood cells (neutrophils, macrophages, and dendritic cells) [R, R, R]
• Producing the B-cells (commonly known as “Bregs”) that suppress defense and autoimmunity [R]
• Helping Tregs block Th17 development [R, R]

The STAT3 protein plays a fine-tuning role in the immune system, as it can both stimulate or suppress the immune response under different circumstances.

STAT3’s Dual Role in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a group of related disorders with chronic inflammation of the digestive tract that causes symptoms such as diarrhea, abdominal pain, bleeding, and weight loss. There are two main types of IBD [R, R]:

• Crohn’s disease: inflammation that can affect the whole digestive tract, especially the small and large bowels.
• Ulcerative colitis: inflammation and sores in the colon and rectum.

Regardless of the type, a typical feature of IBD is the constant activation of STAT3 in both immune and gut lining cells. STAT3 activation can either worsen or improve IBD depending on which cells it is active in, and which messenger molecules are stimulating it [R, R, R, R].

STAT3 activation promotes the survival and development of T-cells — especially Th1 and Th17. These cells maintain inflammation and immune system activation, which could further worsen IBD [R, R, R, R].

In contrast, STAT3 activation in the gut lining promotes wound healing by producing proteins that stimulate the growth and survival of its cells, as well as killing infectious bacteria and reducing inflammation [R, R, R, R].

All in all, it’s not yet clear whether STAT3 is better when it’s higher or lower — in fact, whether it is good or bad highly depends on exactly where in the body it is, and in what type of cells. Nonetheless, some SNPs in the STAT3 gene have been associated with IBD (or certain forms of it), which we’ll discuss in the next section.

STAT3 activation is a typical feature of IBD that can have either positive or negative effects on this condition depending on where and how it is activated. It may worsen inflammation if the protein is activated in T-cells, but may promote wound healing when it is activated in gut lining cells.

The most widely-studied STAT3 polymorphism is rs744166. Although its mechanism remains unknown, some researchers have suggested that certain alleles may alter the structure of the STAT3 protein, which changes how it responds to cytokines [R]. This could disrupt the normal way that the body regulates immune system activity, which may partially explain why this SNP has been associated with an inflammation-related disorder such as IBD.

For example, multiple studies have associated the major ‘A’ allele of rs744166 with an increased frequency of Crohn’s disease [R, R, R, R].

Additionally, among people already diagnosed with IBD, some research also suggests that carriers of the ‘A’ allele for this SNP tend to have more severe cases of IBD than people with other genotypes. For example, two studies observed increased attachment of white blood cells (neutrophils) to the gut lining, as well as increased activation of STAT3 in immature immune cells (CD4+ and innate lymphoid cells) in people with the ‘A’ allele [R, R].

However, this link is stronger in Caucasians. Two studies on Sri Lankan and Jewish populations failed to associate this allele with Crohn’s disease or its symptoms — so it’s possible that the above effects may only apply to certain ethnic groups [R, R].

The ‘A’ allele of rs744166 has also been associated with ulcerative colitis in several studies [R, R, R, R, R].  Nevertheless, two European studies couldn’t associate this variant with ulcerative colitis, so the evidence is still a bit mixed [R, R].

Another polymorphism with an unknown mechanism is rs2293152. Its minor ‘G’ allele has been associated with increased frequency and severity of IBD (Crohn’s disease, ulcerative colitis, or both) in three different studies [R, R, R]. Only one study (in Malaysians) failed to link this polymorphism to IBD [R].

The minor (‘G’) allele of rs4796793 reduces STAT3 expression. In a Chinese population, this allele was less common among people with Crohn’s disease [R, R, R]. This variant was, however, not associated with ulcerative colitis in the same population [R]. Therefore, it is possible that this SNP might only affect certain specific types of IBD, and more research will be needed to clarify this further.

Finally, the major alleles of two less widely-investigated polymorphisms (‘A’ at rs9891119 and ‘T’ at rs3816769) were associated with Crohn’s disease in two studies in Japanese and New Zealander populations [R, R].

The ‘A’ allele of rs744166 and the ‘G’ allele of rs2293152 have been associated with Crohn’s and ulcerative colitis. The major alleles of the polymorphisms rs4796793 (‘C’), rs9891119 (‘A’), and rs3816769 (‘T’) have been only associated with Crohn’s.

You can see your genotype for several STAT3 SNPs in the table below. However, keep in mind that these results are based on association studies suggesting that certain genetic variants are more common in people with IBD, and more research will be needed to know what role (if any) these variants play in actually causing these disorders. Also, many different factors, including other genetic and environmental factors, can influence the risk of inflammatory bowel diseases: therefore, just because you have one of these genotypes does not necessarily mean you are at increased risk of developing IBD!

Primary SNP: STAT3 rs744166:

• ‘A’ = More common in people with IBD.
• ‘G’ = Less common in people with IBD.

Population Frequency:

• Both homozygous genotypes are similarly frequent. 44% of the world population has ‘AG’.
• In European descendants, the frequency of the ‘GG’ genotype is reduced to 19%.

Other Important SNPs:

STAT3 rs2293152:

• ‘C’ =  Less common in people with IBD.
• ‘G’ = More common in people with IBD.

Population Frequency:

• 85% of the world population has at least one ‘C’ allele.
• Only 1% of African descendants have ‘GG’.

STAT3 rs4796793:

• ‘C’ = More common in people with Crohn’s disease.
• ‘G’ = Less common in people with Crohn’s disease.

Population Frequency:

• Both ‘CC’ and ‘CG’ are equally frequent (41% each) in the world population.
• Less than 5% of people with American ancestry have ‘GG’.

STAT3 rs9891119:

• ‘A’ = More common in people with Crohn’s disease.
• ‘C’ = Less common in people with Crohn’s disease.

Population Frequency:

• Almost 46% of the world population has ‘AC’.
• Only 7% of people with American ancestry have ‘CC’.

STAT3 rs3816769:

• ‘T’ = More common in people with Crohn’s disease.
• ‘C’ = Less common in people with Crohn’s disease.

Population Frequency:

• Almost 45% of the world population has ‘TC’. 
• ‘T’ is only slightly more common than ‘C’ in South Asian descendants (51% vs 49%).

If you think you may be experiencing symptoms of IBD, make sure to talk to your doctor so that he or she can diagnose and treat it!

The standard of care for IBD mainly includes anti-inflammatory and immunosuppressant drugs to reduce the underlying inflammation that triggers the symptoms. Some of the standard forms of treatment include:

• Prescription medications (including antibiotics, antidiarrheals, pain relievers)
• A low-fiber diet (to prevent the bowels from becoming blocked)
• Dietary supplements (to treat any nutritional deficiencies caused by IBD)
• Surgery (only used in very severe cases if all other treatments fail to relieve IBD)