Can This Gene Cause Celiac Disease? (ICOS)

The ICOS gene encodes a protein also called ICOS, which is short for ‘Immune co-stimulator’. As its name implies, ICOS participates in an immune process called ‘co-stimulation’. It consists of providing a signal that, together with the presence of an antigen, leads to the full activation of immune cells [R, R, R].

ICOS expression is low in resting CD4+ and CD8+ T cells but is rapidly increased once these cells have been activated. ICOS is involved in multiple key processes of the immune response such as [R, R, R]:

• Promoting T cell activation and proliferation [R, R]
• Activating or blocking Th1 cell development (depending on the pathogen) [R, R, R, R]
• Stimulating the Th2 response [R, R]
• Promoting the formation and maintenance of memory CD4+ T cells [R, R, R]
• Stimulating the T cell-dependent production of antibodies (IgG) by B cells [R, R, R]
• Promoting the development of Tregs [R, R]

People with a defective ICOS variant that impairs the production of the protein suffer from a condition with frequent infections called ‘common variable immunodeficiency syndrome’. The mutation prevents B cell development and antibody production [R, R]. 

Alternatively, variants with imbalanced (often excessive) ICOS activity are associated with immune diseases such as:

• Celiac disease [R, R]
• Rheumatoid arthritis [R, R]
• Lupus [R, R]
• Autoimmune hepatitis [R]

The ICOS gene encodes a protein that activates several processes of the immune response. People lacking ICOS suffer from immunodeficiency, while overactive variants are associated with some autoimmune 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 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].

Other immune cells such as CD8+ and Th17 cells can also recognize gluten and trigger inflammation in response to this protein [R, R].

The CELIAC3 Locus and Celiac Disease

The ICOS gene is located within a region that also contains CD28 and CTLA4, which all belong in the same family. Variants in these three genes are associated with celiac disease and often inherited together. For this reason, the region is often referred to as the CELIAC3 locus [R, R, R, R].

CD28 is a receptor that stimulates T cell activity and development, which helps ramp up immunity and inflammation [R].

CTLA4 helps block T cell responses and lower inflammation [R, 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 ICOS gene and nearby CD28 and CTLA4 are associated with celiac disease, possibly through their effects on T cell activity.

The main polymorphism linked to celiac disease is rs4675374, located in a regulatory region that is removed during the gene expression process (an intron). Mutations in this type of regions may reduce the efficiency of gene expression, resulting in lower levels of the protein [R].

Its minor variant ‘T’ has been associated with susceptibility to celiac disease in a British study and a large-scale study of Finnish, Italian, Dutch, and British populations [R, R].

In a Finnish study on 106 families with celiac disease, the minor variants of 4 other polymorphisms (including rs10932037 and rs10183087) were transmitted from the parents to the offspring [R].

Several ICOS variants located in regions of the gene that regulate its expression have been associated with celiac disease.

SNP Summary and Table

Primary SNP: ICOS rs4675374 

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

Other Important SNPs: 

ICOS rs10932037

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

ICOS rs10183087

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

Population Frequency

The non-risk ‘C’ allele of rs4675374 is clearly more abundant and ~80% of the world population carries at least one copy. Surprisingly, the risky ‘T’ allele is the most common one in African descendents (93% of carriers). In contrast, this variant is especially rare in people with American, European, and East Asian backgrounds.

The ‘T’ allele of rs10932037 is extremely rare and ~88% of the world population doesn’t have any copies. This variant is similarly uncommon in all ethnicities.