HLA-B27: Genetic Variant That Increases Susceptibility to Autoimmune Diseases

Our immune system does an awesome job (most of the time) of fighting off pathogenic bacteria and viruses. But to fight off these pathogens, the body needs to know that they are ‘the bad guys’. This is where the HLA system comes in, sorting out your own cells and proteins as being different than pathogens. When this system breaks down, autoimmune diseases can occur.

This article covers background information on HLA-B27 and how to check your 23andMe or AncestryDNA raw data for the HLA-B27 genotype.

What is the HLA system?

Human leukocyte antigens (HLA) belong to part of our immune system known as the major histocompatibility complex (MHC). The HLA genes code for the proteins that help our body determine what is a foreign invader that needs to be attacked and what is ‘self’.

There are many different HLA serotypes that people can have, giving us all slightly different strengths and weaknesses against microbial diseases.

But along with attacking foreign invaders, a handful of HLA types also increase the susceptibility to autoimmune diseases, where the body attacks its own cells.

HLA-B27 and autoimmune diseases:

People who carry the HLA-B27 serotype are at an increased risk of inflammatory-related autoimmune diseases including:

  • ankylosing spondylitis[ref]
  • reactive arthritis
  • psoriasis
  • inflammatory bowel disease[ref]
  • acute anterior uveitis (inflammation of the eye)[ref]

Post-infectious syndrome for shigellosis, salmonella, and chlamydia is also more common in people who are HLA-B27 positive. This is also known as reactive arthritis.[ref]

What is ankylosing spondylitis (AS)?

Ankylosing spondylitis is a chronic inflammatory disease that mainly affects the spine.  It causes back pain and spinal stiffness, and the vertebrae can fuse together. This often occurs in young adults.  More info can be found on the Spondylitis Association of America site.

Carriers of HLA-B27 are at a 20-fold increased relative risk for the disease. Keep in mind that this is relative risk. For example, if the risk of ankylosing spondylitis is normally 1 in 200 (0.5%), carrying the HLA-B27 variant increases your risk to 20 in 200 (10%).  (These are just example numbers.)

Why is HLA-B27 linked to autoimmune diseases?

There are multiple subtypes of HLA-B27, and the specific types associated with ankylosing spondylitis include HLA-B*2701HLA-B*2702HLA-B*2704HLA-B*2705, and HLA-B*2707.

Not everyone who carries the HLA-B27 serotype will have ankylosing spondylitis. But over 95% of people with ankylosing spondylitis are HLA-B27 positive.

Similarly, over 80% of people with reactive arthritis are HLA-B27 positive.[ref]

Therefore, the HLA-B27 serotype is a big risk factor for these autoimmune diseases, but it doesn’t cause the autoimmune disease by itself.

Instead, there must be other factors involved that trigger the disease, such as toxicant exposure, pathogens, gut microbiome changes, diet, or lifestyle factors.[ref]

Proteins in the body, including the HLA proteins, are made up of amino acids that join together and then fold up in a particular way.  Researchers have found that HLA-B27 has a tendency to misfold.

The specific subtypes of HLA-B27 associated with autoimmune diseases are the ones likely to be misfolded or unfolded, causing problems when formed in the endoplasmic reticulum (ER).

The misfolded or unfolded proteins in the endoplasmic reticulum cause stress in that organelle. Researchers theorized that the body’s unfolded protein response mechanism causes the inflammation.[ref]

HLA-B27 and the immune system:

At one point, researchers advanced a theory that HLA-B27 seemed similar to an infecting bacterial pathogen and thus caused autoimmune diseases. The idea is called ‘molecular mimicry’ and the idea reasons the immune system attacks ‘self’ thinking it is a bacteria. (Some nice YouTube videos explaining ankylosing spondylosis state that this is the reason for it…)

The problem is newer research shows that you can create ankylosing spondylitis in an animal model without the T-cells needed for attacking a pathogen. Thus, researchers now are uncertain whether molecular mimicry is the cause of ankylosing spondylitis .[ref][ref]

Recent research shows that the IL-23/IL-17 inflammatory pathway is likely involved in many of the spondyloarthritis-associated autoimmune diseases for which HLA-B27 increases the risk. TNF-alpha, another inflammatory cytokine, may also increase the risk of these spondyloarthritis-associated autoimmune diseases.[ref]

Related article: Genetic variants that increase TNF-alpha

Researchers theorize that the HLA-B27 protein often misfolds, which triggers the cells to initiate what is called the unfolded protein response. Essentially, this is the process by which proteins that aren’t formed correctly are broken down and the amino acids recycled. When this unfolded protein response is activated too often, such as can happen with HLA-B27, it triggers the inflammatory response with the IL-23/IL-17 pathway. [ref]

Protection from viral infections:

A lot of ‘bad’ mutations exist in the genome because they also create a benefit for survival. For example, a mutation that helps someone survive a pathogenic outbreak of cholera means the person carrying the mutation lives to pass it on to their kids. Much of our genome is sculpted by surviving against bacterial or viral pathogens; if our ancestors hadn’t survived, we wouldn’t be here today.

Interestingly, carriers of the HLA-B27 have a survival advantage and are likely to live longer with hepatitis C infections and with HIV.[ref][ref]

Additionally, people with the HLA-B27 serotype may mount a better response against the Epstein-Barr virus. [ref]


Check your genetic raw data for HLA-B27:

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Genetic variants included in 23andMe data coding for HLA-B27 are listed below.

These variants show if you are likely to carry an HLA-B27 type.  A blood test is still needed to be 100% certain that you carry the exact HLA-B27 type associated with autoimmune diseases.

Check your genetic data for rs4349859(23andMe v5 only; AncestryDNA):

  • A/A: high likelihood of carrying 2 copies of HLA-B27[ref][ref][ref]
  • A/G: high likelihood of carrying 1 copy of HLA-B27
  • G/G: typical

Members: Your genotype for rs4349859 is .

Check your genetic data for rs13202464 (23andMe v4,v5; AncestryDNA):

  • G/G: high likelihood of carrying 2 copies of HLA-B27[ref][ref][ref]
  • A/G: high likelihood of carrying 1 copy of HLA-B27
  • A/A: typical

Members: Your genotype for rs13202464 is .


Lifehacks:

Keep it in perspective:

Don’t freak out if you are a carrier of HLA-B27. Instead, use this information as a heads up not to ignore health issues such as back pain.

Blood tests to confirm:

If you want to get the blood test for HLA-B27 and you can’t get it through your doctor, you can order it on your own in the US. UltaLab Tests is one place that I use. There are other websites as well, so shop around for the best price.

Understanding the risk:

Although HLA-B27 increases the relative risk of ankylosing spondylosis by 20-fold, it is still a rare disease with about 1 in 2000 people having it.[ref] If you have the HLA-B27 serotype, the lifetime absolute risk is about 6-10%.[ref]

There are other genetic variants thought to be involved in susceptibility to ankylosing spondylosis, as well as environmental factors that increase the risk.[ref]

Reactive Arthritis and antibiotics:

If you carry the HLA-B27 type and also have reactive arthritis, there is an interesting tie to salmonella persistence or other microbial infections. You may want to read more on both topics or talk with your doctor about treatment options for persistent bacterial infections.

Gut microbiome connection to HLA-B27:

There is also a connection between HLA-B27 and changes to the gut microbiome.[ref]

Interestingly, spondylitis patients also showed changes in the gut microbiome with decreased F. prausnitzii and increased Bacteroides fragilis.[ref] You may want to consider getting a gut microbiome test to see if everything is in order down there.

Probiotics for HLA-B27:

Animal studies show that Lactobacillus G/G probiotics may help with preventing recurrence of inflammatory bowel problems associated with HLA-B27.[ref]  Although I couldn’t find a human clinical trial on Lactobacillus G/G specific to people with HLA-B27, if you are wanting to try a Lactobacillus G/G probiotic, the Culturelle brand probiotic contains that strain.

Autoimmune Paleo (AIP) diet:

The link between diet and symptoms of reactive arthritis or ankylosing spondylitis isn’t clear.  A meta-analysis combined the results of a bunch of studies on the subject and found no statistical links with diet.[ref]

On the the other hand, individuals report anecdotally that diet can make a difference. Some find that certain foods make their joint pain worse. Thus, trying an elimination diet or the autoimmune protocol diet may be worthwhile.

 


Related Genes and Topics:

CTLA-4 – General Autoimmune Risk Factor
The CTLA4 gene codes for a protein that is important in the immune system. It acts as a checkpoint that can downregulate your immune system response. Genetic variants in the CTLA4 gene can increase your risk for several different autoimmune diseases.

Genes and Back Pain
The majority of people by middle age have disc degeneration, but not everyone has pain from it. Your genes play a big role in whether you will feel the pain and inflammation in your back. Understanding the genes involved may be a guide for the right treatment.

Psoriasis Genes
Psoriasis is an autoimmune condition that causes dry, sometimes itchy patches of skin. It is caused by the immune system attacking your skin cells, speeding up the turnover of the cells. Genetics plays a role in your susceptibility

Rheumatoid Arthritis Genes
Rheumatoid arthritis is caused by an immune system attack on the joints, causing thickening and inflammation of the joint capsule. It is caused by a combination of genetic susceptibility and environmental triggers.

 

Originally published 07/2018. Updated 1/2020.




Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.