Genetic Background of Autoimmune Gut Inflammation (HLA-DRB1)

The HLA System

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

HLA genes come in many different forms, and there are millions of their possible combinations. Their diversity ensures the 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 foreign structures from our bodies. These genes have a well-known connection with different autoimmune disorders.

HLA-DRB1

The HLA system has three groups or classes; HLA-DRB1 belongs to class II. These receptors present outside peptides (antigens) to T-helper cells, triggering the immune response to attack and neutralize them [R].

The HLA-DRB1 gene encodes the beta chain, which merges with the alpha chain to form the HLA-DR receptor. Hundreds of DRB1 variants (alleles) can change the structure and activity of this receptor and thus impact the immune response [R].

HLA-DRB1 encodes one part of the receptor that presents antigens to T-helper cells and triggers the immune response against them. Different genetic variants can change their structure and activity.

The Role of HLA-DRB1 in 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].

HLA-DRB1 plays a vital role in gut health by controlling the immune response against pathogens. It presents pathogenic peptides to white blood cells, enabling their removal [R].

However, specific types of this receptor may mistakenly flag our own peptides and thus contribute to autoimmune gut inflammation [R].

Crohn’s disease and ulcerative colitis are two forms of IBD. HLA-DRB1 flags pathogenic peptides in the gut, but it may also play a role in autoimmune gut inflammation.

The HLA complex is a part of IBD3, a genetic region strongly associated with both Crohn’s disease (CD) and ulcerative colitis (UC) across different populations [R, R, R].

This region accounts for 10-33% of the total genetic risk for Crohn's and 64%-100% for UC [R, R].

Rs2395185

In a meta-analysis of over 3,600 subjects, the “T” allele at rs2395185 correlated with 50% lower rates of ulcerative colitis. A more comprehensive meta-analysis (n=9,484) confirmed this effect [R, R].

A study of 1,500 Indian subjects came to the same conclusion: UC was over 50% less common among the “T” allele carriers [R].

In a trial of 94 IBD patients, the “G” allele was associated with a poor response to anti-TNF treatment. In people with this allele, the treatment had 4.6x higher chances of failure [R].

The “T” allele at rs2395185 is associated with lower rates of ulcerative colitis and a better response to IBD treatment.

Rs3763313

The “C” allele at rs3763313 is associated with 19% higher rates of Crohn’s disease, according to a meta-analysis of three studies and over 15,000 European subjects [R].

Another meta-analysis with nearly 9.5K European participants linked the same allele with ulcerative colitis [R].

Rs9271366

This variant showed a strong correlation with ulcerative colitis (UC) in different populations, including [R, R, R]:

• Afro-American
• Japanese
• Korean

Among 3,308 Afro-American subjects, those with the “G” allele at rs9271366 had 60% higher UC rates [R].

How It Works

Scientists are still figuring out the exact mechanism by which HLA class II genes impact IBD. There are many different variants in this region, and it's hard to tell which one plays an actual role in autoimmune gut inflammation.

Alleles marked by the SNPs we discussed can change the structure of HLA-DR receptors, causing them to confuse healthy proteins in the gut for pathogenic ones. This phenomenon is known as “molecular mimicry” and may lead to autoimmunity [R].

Rs2395185 marks the allele HLA-DRB1*1101, while rs9271366 marks HLA-DRB1*1502. Both alleles may have a functional role in IBD by changing the HLA-DR structure. Additionally, the “G” allele at rs2395185 was associated with higher expression of HLA-DRB1 and DQA1 genes [R, R, R].

These variants don't strictly belong to the HLA-DRB1 gene. They are located in the region that encompasses more genes, including BTLN2 and HLA-DQ genes [R].

The above SNPs mark the alleles that may change the structure and activity of different HLA class II genes. These changes can contribute to autoimmune gut inflammation, the hallmark of IBD.

SNP Summary and Table

Primary SNP:

HLA-DRB1 rs2395185

• ‘G’ = associated with a poor response to IBD treatment
• ‘T’ = associated with lower rates of ulcerative colitis

Population Frequency: Around 54% of European and East Asian descendants carry at least one copy of the “T” allele. It’s less common in African populations (34%).

Other Important SNPs:

HLA-DRB1 rs3763313

• ‘A’ = not associated with ulcerative colitis or Crohn’s disease 
• ‘C’ = associated with higher rates of ulcerative colitis and Crohn’s disease

Population Frequency: Between 38-44% of people carry at least one copy of the “C” allele across all populations.

HLA-DRB1 rs9271366

• ‘A’ = not associated with ulcerative colitis 
• ‘G’ = associated with higher rates of ulcerative colitis

Population Frequency: Around 22% of European and African descendants carry the “G” allele. It’s a bit more common in East Asian populations (29%).