Is HLA-B27 the only gene responsible for Ankylosing spondylitis?

We have already seen in the previous posts that HLA-B27 is the most common gene associated with Ankylosing spondylitis (AS). However, HLA-B27 does not seem to be the only gene associated with AS.

Strong indicators of this fact include-
1. AS can occur in individuals who do not carry HLA-B27 gene.
2. Amongst the HLA-B 27 individuals, only about 1-5% individuals develop AS.
3. HLA-B27 positive relatives of AS patients have a risk of developing AS that is 5.6 to 15 times that of HLA-B27 positive individuals in general population. This would mean that there are other non HLA-B27 familial genetic factors involved in causation of AS.

There has been some major work by the Wellcome trust case Control Consortium
& Australo-Anglo-American Spondyloarthritis Consortium to look into the genetics of AS. These (& other) studies have revealed that there are other genes & genetic loci responsible for Ankylosing spondylitis as well—
1. HLA-B60 seen in HLA-B27 positive as well as negative AS patients.
2. HLA-B 39 seen in HLA-B27 negative patients
3. ERAP-1— endoplasmic reticulum aminopeptidase-1
4. Interleukin-23 receptor gene—IL-23R
5. RUNX3
6. KIF21B
7. 2p15
8. IL12B
10. 21q22
11. ANTXR2
12. PTGER4
13. CARD9
14. TBKBP1

Out of these genes, ERAP-1 & IL-23 R have generated maximum interest. The researchers have found that some variants of ERAP1 protect against the development of Ankylosing spondylitis. For individuals who carry HLA-B27, their risk of developing Ankylosing spondylitis decreases by a factor of four if they carry two copies of the protective variant of ERAP1.

HLA-B27 presents the pathogen antigen to the immune cells. The ERAP-1 gene interacts with HLA-B27 to affect how these peptides are presented to the immune system. The researchers have found that some variants of ERAP1 protect against the development of Ankylosing spondylitis by reducing the amount of peptide available to HLA-B27 within cells. This could prove to be a target for treatment in the future.

Tests for these genetic markers are not available routinely as of now. But, then, if they are found to be clinically useful; tests should be available in the future.

1. Investigating the genetic association between ERAP1 and ankylosing spondylitis. Harvey D & colleagues. Hum Mol Genet. 2009 Nov 1;18(21):4204-12.
2. Progress in the genetics of ankylosing spondylitis. Matthew A brown. Briefings in Functional Genomics (2011) 10 (5): 249-257.
3. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. The Australo-Anglo-American Spondyloarthritis Consortium (TASC), the Wellcome Trust Case Control Consortium 2 (WTCCC2), Nature Genetics 43, 761–767 (2011)


  1. I’m always wary of articles relating genetics and ankylosing spondylitis because they are so dismissive of HLA-B27-negative patients. Have we been misdiagnosed or are we insignificant? It seems to me that genetic answers lie in aberrations rather than commonalities. Why do some patients who do not carry HLA-B27 develop Ankylosing Spondylitis? Most articles I’ve seen begin with the supposition of what genes in addition to HLA-B27 affect AS, rather than attempting to research why people without it develop the disease. That’s where the cure will be revealed. We’re looking in the wrong places, with the wrong assumptions. If you also assume that most AS patients have dark hair, would you confine your research to hair color?



  2. yep… I am tired of taking NSAIDs and DMARDs and waiting for the real breakthrough (not like anti-tnf which perhaps bit more than I can afford and isn’t foolproof).

    P.S – I am HLA-B27 +ve btw.



      1. Thanks, doctor akerkar. indeed, it’d be great for patients like me. I am keeping my fingers crossed and try to be up to date for researches in this area.



  3. sir,i suffering from infammation of my ankle,knee and elbow with severe penetrating pain,my hlab27 was +ve ,i take inmecin tds but condition same,sir plz suggest me



    1. Dear Manoj,

      You seem to have Seronegative spondyloarthropathy.

      Inmecin is a NSAID & not the final solution for the same.

      You should see a Rheumatologist. He would start DMARDs (Sulphasalazine/ methotrexate) to take care of the arthritis.



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