The Key Genetic Factor for Celiac Disease (HLA-DQ)

The HLA System

The human leukocyte antigen (HLA) system is a group of human genes encoding HLA proteins. These proteins are also referred to as major histocompatibility complex (MHC) proteins. HLAs are receptors, found on the surface of white blood cells. They help flag and remove agents that may harm the body or cause infections. These harmful agents are known as antigens [R].

HLA genes come in many different forms, and there are millions of possible HLA combinations. Their diversity ensures protection against a wide array of external threats, but it can be a double-edged sword: HLA variants correlate with different autoimmune disorders [R, R].

The HLA system encodes receptors that help flag and remove external threats from our bodies. These genes have a well-known connection with different autoimmune disorders.

HLA-DQ

The HLA system has three groups or classes; HLA-DQ belongs to class II. These receptors present outside peptides (antigens) to T-helper cells. Upon this signal, T-helpers stimulate B cells to make antibodies to specific antigens, which attack and neutralize them [R].

The HLA-DQA1 gene codes for an alpha subunit of one such receptor. Along with a beta subunit, encoded by HLA-DQB1, it forms a so-called DQ(αβ) heterodimer to present foreign proteins to the immune system [R, R].

Celiac disease is an immune gut disorder in which gluten, a protein found in most grains, damages the small intestine. The immune cells recognize gluten as a threat and trigger an aggressive inflammatory response, usually causing digestive issues and malabsorption [R, R].

Gluten intolerance is a condition in which the body can’t digest gluten well. It results in similar digestive symptoms, but, unlike celiac disease, it may not cause inflammation or damage the gut [R].

Most people with celiac disease can manage the symptoms by following a strict gluten-free diet.

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 Link With HLA-DQ

Scientists were able to confirm a direct role in celiac disease development for HLA-DQA1 and HLA-DQB1 genes [R, R].

Different alleles in these genes can produce different types of HLA-DQ structures. The DQ2 type (especially the DQ2.5 subtype) is present in up to 98% of celiac disease patients, depending on the population. That is among the strongest known links to autoimmunity in the entire HLA system [R, R].

Still, the DQ2 structure is common among healthy people, indicating that other genetic and environmental factors also play a role in CD development [R, R]. For example, the DQ8 receptor is the second most common type among gluten-intolerant people [R, R].

Specific alleles in the HLA-DQA1 and HLA-DQB1 genes encode DQ2 and DQ8 receptors, present in the vast majority of celiac disease patients.

DQ2.5

Scientists have identified a variant that marks DQ2.5, responsible for most celiac disease cases: the “T” allele at rs2187668 [R].

A study of over 27,000 subjects identified this SNP as the primary genetic factor for celiac disease. People carrying the “T” allele had over six times higher chances of being diagnosed with celiac disease [R].

A smaller trial of 889 participants came to a similar conclusion [R].

The HLA gene region has been associated with other autoimmune conditions, including:

• Lupus [R, R]
• Autoimmune hepatitis [R]
• Multiple sclerosis [R]
• Graves’ disease [R]
• Type 1 diabetes [R]

The “T” allele at rs2187668 marks DQ2.5; people with this allele may have over six times higher rates of celiac disease.

DQ8

The HLA-DQ8 type is the second most common in celiac disease patients. Most patients carry both DQ2.5 and DQ8, but DQ8 may help identify additional patients negative for DQ2.5 [R].

Researchers found an SNP that marks DQ8 with great precision: rs7454108. People with the “C” allele almost certainly carried this HLA receptor type [R].

How It Works

Two alleles — DQA1*0501 and DQB1*0201 — form the DQ2.5 haplotype, which codes for the DQ2.5 receptor on white blood cells. The DQ2.5 receptor binds gluten and presents it to T-helper cells, initiating widespread gut inflammation [R, R].

Additionally, the DQ2.5 haplotype may increase DQ2.5 receptor expression, further contributing to inflammation [R].

rs2187668-A serves as a genetic marker — it tags the DQ2.5 haplotype with high precision. In other words, the vast majority of people with the “A” allele will have this haplotype and thus be predisposed to celiac disease [R].

The alleles DQA1*03 and DQB1*0302 form the DQ8 haplotype, coding for the second most common HLA receptor activated by dietary gluten. Carriers of the “C” allele at rs7454108 likely have this haplotype, which may put them at risk of celiac disease [R].

The DQ2.5 receptor, marked by rs2187668-A, presents gluten peptides to the immune cells, which may trigger widespread gut inflammation. The DQ8 receptor, marked by rs7454108-C, can cause a similar reaction but to a lesser extent.

SNP Summary and Table

Primary SNP:

HLA-DQA1/B1 rs2187668

• ‘C’ = not associated with celiac disease
• ‘T’ = associated with significantly higher rates of celiac disease

Population Frequency: Around 20% of European descendants carry the “T” allele; its frequency in other populations is 10-15%.

Other Important SNPs:

HLA-DQA1/B1 rs7454108

• ‘T’ = not associated with celiac disease
• ‘C’ = associated with higher rates of celiac disease

Population Frequency: Unavailable