HLA-B27: Genetic Variants That Increase Susceptibility to Autoimmune Diseases

HLA-B27 - check your 23andMe or AncestryDNA

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.

This article covers background information on HLA-B27 and the genetic variants available in 23andMe or AncestryDNA data.

What is the HLA system?

Human leukocyte antigens (HLA) is the 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 is linked to susceptibility to inflammatory-related autoimmune diseases including:

  • ankylosing spondylitis[ref]
  • reactive arthritis
  • psoriasis
  • inflammatory bowel disease[ref]
  • acute anterior uveitis

post infectious syndrome for shigellosis, salmonella, and chlamydia is more common in HLA-B27 positive.

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 risk for the disease.

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 AS carry HLA-B27.  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 are must be other factors – environmental, pathogens, gut microbiome, diet? – that are involved. [ref]

Everyone has multiple HLA serotypes that are essential for combating pathogens. So why is this HLA-B27 more likely to lead to autoimmune conditions?

At one point, researchers advanced a theory that HLA-B27 was similar to an infecting bacterial pathogen. The idea is called ‘molecular mimicry’ and the idea is that the immune system attacks ‘self’ thinking that it is a bacteria. (Some nice YouTube videos explaining ankylosing spondylosis state that this is the reason for it…)  The problem is that newer research shows that you can create AS in an animal model without the T-cells needed for attacking a pathogen, so there is uncertainty as to whether this is actually a cause of AS.  [ref][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 ones that are likely to be misfolded or unfolded, causing problems when they are formed in the endoplasmic reticulum (ER). The misfoleded or unfolded proteins in the ER cause stress in that organelle, possibly causing inflammation due to an unfolded protein response mechanism.[ref]

 


Genetic Variants:

Genetic variants included in 23 and Me data that code for HLA-B27 are listed below. These variants show if you are likely to carry an HLA-B27 type. There are several subtypes of HLA-B27 and not all of them cause a higher risk of inflammatory autoimmune diseases. A blood test is still needed to be 100% certain that you carry the 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: normal

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: normal

 



Lifehacks:

Keep it in perspective:
Don’t freak out if you are a carrier of HLA-B27. In Caucasians, about 10% of people carry one copy, whereas only 1% of African populations carry HLA-B27.[ref]

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.

Although HLA-B27 increases the 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%.[ref]  There are other genetic variants thought to be involved in the risk for ankylosing spondylosis,  as well as environmental factors.[ref]

Survival advantage:
Interestingly, carriers of the HLA-B27 have a survival advantage for HIV and hepatitis C.[ref]

Gut Microbiome:
There is also a connection between HLA-B27 and changes to the gut microbiome.[ref] Spondylitis patients also showed changes in the gut microbiome with decreased F. prausnitzii and increased Bacteroides fragilis.[ref] You may want to get a gut microbiome test done to see if everything is in order down there.

Reactive Arthritis:
If you carry the HLA-B27 type and also have reactive arthritis, there is an interesting tie to salmonella persistence or other microbial infections.

Probiotics:
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 it, if you are wanting to try a Lactobacillus G/G probiotic, Culturelle contains that strain.

Autoimmune Paleo (AIP) diet:
The link between diet and symptoms of reactive arthritis or ankylosing spondylitis isn’t clear.  A meta-study looked at a bunch of studies on the subject and found no statistical links with diet. But individuals report that diet can make a difference in their joint pain with certain foods making it worse.  So 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.

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

 

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. 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 scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.