Can This Gene Cause Gut Inflammation? (BACH2)

The BACH2 gene encodes one of the two members of the BACH (‘Bric-a-brac, tramtrack and broad complex and cap n′ collar homology’) family. BACH proteins bind to DNA to turn ‘off’ the expression of specific genes [R].

BACH2 is mainly expressed in B cells and T cells and is involved in the development of these cell types [R, R, R, R].

In B cells, BACH2 delays their development and increases their time window to produce high-affinity antibodies (IgG) against viruses and bacteria [R, R, R, R]. 

Depending on the T cell subtype, BACH2 can [R]:

• Finetune Th1 development through a complex network of genes that stimulate and inhibit it [R, R, R].
• Block the development and inflammatory responses of Th2 cells [R, R].
• Stimulate the production of anti-inflammatory cytokines (IL-9 and IL-10) by Th9 cells [R].
• Block the development and inflammatory response of Th17 cells [R, R].
• Promote the development, activity, and survival of anti-inflammatory Tregs [R, R].

All in all, BACH2 helps control the correct functioning of the immune system, mainly by reducing inflammatory responses. Variants that alter its activity have been associated with different immune and inflammatory conditions such as:

• Celiac disease
• IBD (especially Crohn’s) [R, R, R]
• Autoimmune thyroid disease [R, R, R] 
• Rheumatoid arthritis [R, R]
• Multiple sclerosis [R, R]
• Addison’s disease [R, R]
• Lupus [R]
• Vitiligo [R]
• Asthma [R]
• Type 1 diabetes [R, R, R, R]

Similarly, reduced BACH2 expression has been observed in the blood of people with multiple sclerosis, lupus, and chronic pancreatitis while ulcerative colitis was associated with higher BACH2 levels [R, R, R, R].

The BACH2 gene encodes a protein that regulates the development of immune cells by turning ‘off’ certain genes. Alterations in its activity have been associated with different immune and inflammatory conditions, including celiac disease.

BACH2 and Celiac Disease

Celiac disease is an immune disorder triggered in response to gluten, a protein found in grains such as wheat, barley, and rye. The immune cells recognize gluten as a threat and mount an aggressive inflammatory response that damages the small intestine and causes digestive issues and nutrient deficiencies due to poor absorption [R, R].

More specifically, the activation of immature CD4+ T cells by gluten causes their development into Th1 cells and the release of inflammatory cytokines such as IFN-γ and IL-21 [R, R, R, R].

The role of BACH2 in regulating the development of Th1 cells may explain the abundance of polymorphisms at this gene associated with celiac disease, as will be discussed below. In line with this, a transcriptomic analysis found reduced BACH2 expression in T cells from celiac patients [R].

Celiac disease is a disorder in which the immune system causes inflammation and damages the small intestine in response to gluten, a protein found in most grains. The BACH2 protein may protect from it by preventing the development of Th1 cells.

Celiac Disease

Several variants of the BACH2 gene involved in celiac disease have been identified, although none of them has been extensively investigated.

The minor allele ‘G’ at rs11755527 was associated with celiac disease in a British and Dutch study. This variant has also been associated with type 1 diabetes in Pakistani but not in Brazilian populations [R, R, R, R, R]. 

The minor variant ‘A’ at another polymorphism, rs10806425, was associated with celiac disease in 5 European (British, Finnish, Dutch, and Italian) populations [R].

Another minor variant (‘C’ at rs7753008) was associated with this condition in a study on population samples from Spain, Poland, Italy, UK, Netherlands, and India [R].

In contrast, the minor allele ‘C’ of rs2474619 was protective against celiac disease in the same study. Interestingly, its major variant has been linked to autoimmune hyperthyroidism (Grave’s disease) [R, R].

Although these studies didn’t measure BACH2 activity, we can speculate that most of these variants reduce it based on the association of low BACH2 levels with celiac disease [R]. 

Inflammatory Bowel Disease

The role of BACH2 in IBD has been less widely researched.

A large meta-analysis of 6 studies (with populations from Germany, Belgium, UK, and US) identified the major allele ‘C’ at the rs1847472 polymorphism as a susceptibility variant for Crohn’s disease. This variant also increased the risk of recurrence after the surgical removal of affected bowel regions in a Canadian study [R, R].

The authors of the second study speculated that this variant may cause an inappropriate immune response against beneficial gut bacteria, thus preventing the restoration of the gut flora, by altering the production of antibodies by B cells [R].

Anecdotally, a study of British children with IBD identified two rare BACH2 variants in two children with ulcerative colitis [R].

Several BACH2 variants that possibly reduce its activity have been associated with celiac disease and, in some cases, other immune conditions. Another variant was associated with Crohn’s disease incidence and recurrence.

SNP Summary and Table

Primary SNP: BACH2 rs11755527 

• ‘C’ = Normal risk of celiac disease.
• ‘G’ = Increased risk of celiac disease.

Population frequency: 85% of the world population carries the ‘C’ allele. The minor variant is especially rare in African descendants (only 3.5% of ‘GG’).

Other Important SNPs: 

BACH2 rs10806425

• ‘C’ = Normal risk of celiac disease.
• ‘A’ = Increased risk of celiac disease.

Population frequency: 90% of the world population carries the ‘C’ allele. ‘A’ is most common among European descendants and rarest in people with an African background.

BACH2 rs7753008

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

Population frequency: Almost 67% of the world population carries two copies of the major allele ‘T’ The ‘C’ allele is almost non-existent in people of East Asian ancestry, while 62% of European descendants carry at least one copy.

BACH2 rs2474619 

• ‘A’ = Normal risk of celiac disease.
• ‘C’ = Reduced risk of celiac disease.

Population frequency: Less than 8% of the world population carries two copies of the ‘C’ allele. This variant is almost non-existent in people of African descent but more common in East Asian and European descendants.