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
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)