Ankylosing Spondylitis: Who Gets It?
GENES THAT ARE INVOLVED
Ankylosing Spondylitis has a strong association with the HLA molecule, specifically HLA-B27, which is a gene found in approximately 90%-95% of patients. In fact, the association of B27 to AS is among the strongest associations known between a gene and a disease.
This gene does not only exist among those with Ankylosing Spondylitis. Many people in the population have this gene (about 8% among Caucasians, and 24% among those in Northern Scandanavia), which means they are SUSCEPTIBLE to developing the disease, and yet some never do develop the disease. In fact, only about 20% of these individuals actually end up developing the disease (3).
Therefore, the gene or genes alone are not the only component involved in determining who will actually develop AS. It is thought to be triggered by exposure to a common environmental pathogen, such as the Klebsiella bacteria.
Although 50% of the overall risk for developing AS is thought to be due to the HLA-B27 gene, there are other HLA genes believed to be involved. For example, the combination of HLA-B27 with HLA-B60 and HLA-B35 have been found to increase the genetic predisposition of developing Ankylosing Spondylitis by sixfold! (1,2) Other HLA genes implicated are HLA-B40:01, HLA-B52, and HLA-B38.
And even among the B27 alleles, different combinations seem to have different strengths of association with AS. For example, HLA-B27:02 (Mediterraneans), HLA-B27:04 (Asians), and HLA-B27:05 (Caucasians and American Indians), are strongly associated. There are other subtypes of the HLA-B27 gene that have been found in patients with AS, although their association to the disease is not as common (HLA-B27:01, B27:03, B27:07, B27:08, B27:10, B27:13, B27:14, B27:15, B27:19, and B27:25). Any other allele combinations of HLA-B27 linked to Ankylosing Spondylitis are very rare besides these mentioned (5).
There are a number of studies that have shown some non HLA genes are also associated with Ankylosing Spondylitis. By means of genome wide studies, IL23R and ERAP1 were also discovered to have a link to AS.
Because of the genomes found to be linked, it is now generally viewed that AS is polygenic in character, but HLA-B27 is still found to have the strongest link to the disease. Even among those who are told they are HLA-B27 negative, a portion of these patients who were re-tested by a different lab at a different time were then found to be positive. Dr. Ebringer in London who studied Ankylosing Spondylitis for many decades said that up to 50% of his patients who were previously told they were HLA-B27 negative were, in fact, found to be positive upon retesting.
Because of the strong association of the HLA-B27 gene and Ankylosing Spondylitis, testing for this gene can be helpful in forming a diagnosis, when other classic symptoms are also present. However, if the test shows negative for HLA-B27, this should not rule out AS as a possible diagnosis.
HOW DO GENES CAUSE THE DEVELOPMENT OF ANKYLOSING SPONDYLITIS?
As mentioned, although the exact mechanism for how the genes affect the manifestation of the disease is not fully understood, there is scientific evidence that molecular mimicry is at play, implicating the antigens for the Klebsiella bacteria (3). These antigens closely resemble the HLA-B27, resulting in the body’s own immune system mis-identifying the tissue of the human body as being the bacteria involved, and launching attacks against said tissue (3).
When rats are given the HLA-B27 gene, and they are raised in a sterile germ-free environment, they do not develop gut or joint inflammation. Again, this supports the conclusion that environmental bacterial pathogens are involved in triggering the symptoms in genetically susceptible individuals (4), and it provides evidence that the gut flora plays a significant role in the joint and gut inflammation associated with the HLA-B27 gene.
HOW COMMON IS ANKYLOSING SPONDYLITIS, & WHAT ARE MY CHANCES OF GETTING IT?
The prevalence of Ankylosing Spondylitis corresponds to the presence of HLA-B27 in the different ethnic groups which have been studied. As an example, African Blacks with unmixed ancestry are not known to carry the HLAB27 gene, and this correlates to the fact that AS is very rare among them. By contrast, particular Athabascan Indian tribes of North America who have a very high occurrence of HLA-B27 also have a high prevalence of AS. These associations between the prevalence of HLA-B27 and the prevalence of AS definitely suggest that the HLA-B27 gene is involved in the development of the disease (3).
As noted earlier, however, over 80% of those who have the HLA-B27 gene do not develop the symptoms associated with Ankylosing Spondylitis. Since 8% of the general caucasian population have the gene, let’s put this into practical terms.
Based on the current population of the USA (325,771,242 as of 2018), that means there are 26 million individuals who carry the HLA-B27 gene (that’s 8%). Twenty percent of these gene-carriers are expected to develop AS, which translates into 5.2 million people.
In the UK, the population (as of 2018) is 66,404,468. Eight percent of the population are expected to carry the HLA-B27 gene, which would be 5,312,357 people. Of those, 20% will likely develop Ankylosing Spondylitis. This translates into 1,062,471 people.
Together, that means that over 6.2 million patients suffer from AS just in the USA and UK combined. This does not count all the other countries of the world. Some people categorize AS as a “rare disease”, but we can see from these numbers that it hardly qualifies.
How about men vs women? Earlier studies indicated that the ratio of men to women who have AS is 9 to 1. But more recent studies show that now, the ratio is 2 to 1, or maybe 3 to 1. This means that there are millions of women who have Ankylosing Spondylitis, and probably more than are reported, because women are misdiagnosed even more frequently than men. This is often because their symptoms present slightly different than the symptoms most men experience, or it is because Doctor's diagnose them with fibromyalgia instead of AS, or because they are under the outdated impression that AS is a "man's disease".
1. Robinson WP, van der Linden SM, Khan MA, Rentsch HU, Cats A, Russell A, et al. HLA-Bw60 increases susceptibility to Ankylosing Spondylitis in HLA-B27+ patients. Arthritis Rheum1989;32:1135–41.
2. Said-Nahal R, Miceli-Richard C, Berthelot JM, Duche A, Dernis-Labous E, Le Blevec G, et al. The familial form of spondylarthropathy: a clinical study of 115 multiplex families. Groupe Francais d’Etude Genetique des Spondylarthropathies. Arthritis Rheum2000;43:1356–65.
3. Alan Ebringer, Taha Rashid, Clyde Wilson, Teresa Ptaszynska, and Mark Fielder. Ankylosing Sponylitis, HLA-B27 and Klebsiella – An Overview: Proposal for Early Diagnosis and Treatment. Current Rheumatology Reviews 2006, 2: 55-68.
4. Taurog JD,Richardson JA,Croft JT et al. The Germfree State Prevents Development of Gut and Joint Inflammatory Disease in HLA-B27 Transgenic Rats. J Exp Med 1994; 180: 2359-64.
5. Taurog JD, The Mystery of HLA-B27: If It Isn’t One Thing It’s Another. ARTHRITIS & RHEUMATISM Vol. 56, No. 8, August 2007, pp 2478–2481 DOI 10.1002/art.22807.
6. Arthritis & Rheumatism (Arthritis Care & Research), Vol. 59, No. 3, March 15, 2008, pp 449–454, DOI 10.1002/art.23321