Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the spine and the sacroiliac joints. This condition can lead to persistent pain and stiffness, and in some cases, it may result in new bone formation and eventual fusion of the vertebrae. While the exact cause of AS is not fully understood, research indicates that genetic factors play a significant role in its development.
The Primary Genetic Link
The most prominent genetic association with ankylosing spondylitis is the Human Leukocyte Antigen B27 (HLA-B27) gene. This gene is part of the HLA complex, which helps the immune system distinguish the body’s own proteins from foreign invaders. HLA-B27 is found in 80% to 90% of individuals with AS. In contrast, this gene is present in only about 5% to 10% of the general population. Despite its strong association, carrying the HLA-B27 gene does not guarantee the development of AS, as only about 5% to 10% of HLA-B27 positive individuals will develop the condition. This gene is estimated to contribute approximately 20% to 30% of the overall genetic risk for AS.
Other Genetic Contributions
Ankylosing spondylitis is considered a polygenic disease, meaning that multiple genes, not just HLA-B27, contribute to an individual’s risk. Genome-wide association studies have identified over 100 genetic regions linked to AS susceptibility. Notable examples include ERAP1 and IL23R. ERAP1 is involved in processing peptides for presentation by HLA-B27, and its association with AS is often restricted to individuals who are also HLA-B27 positive. IL23R is a key component of the IL-23/IL-17 signaling pathway, which is central to inflammation in AS. The combined effect of these genes, along with HLA-B27 and environmental factors, collectively increases an individual’s susceptibility to developing AS.
Genetic Testing and Family Risk
HLA-B27 testing may be performed to assist in diagnosing ankylosing spondylitis, especially when a person presents with ambiguous symptoms. However, a positive HLA-B27 test alone does not confirm an AS diagnosis. Conversely, a negative test does not rule out the disease, as a small percentage of individuals with AS do not carry the HLA-B27 gene.
Ankylosing spondylitis has a strong familial component, with heritability over 90%. First-degree relatives of individuals with AS have a 4% to 11% chance of developing the condition. If a parent with AS carries the HLA-B27 gene, there is a 50% chance they will pass this gene to their child. However, only about 5% to 20% of children who inherit the HLA-B27 gene from an affected parent will develop AS. Genetic testing therefore provides information about a predisposition, rather than a definitive diagnosis or certainty of developing the disease.
How Genes Influence Disease Development
The precise mechanisms by which genes contribute to ankylosing spondylitis development involve an intricate interplay between genetic predisposition and environmental factors. Environmental triggers, such as the gut microbiome and certain infections, are believed to interact with genetic variations to initiate the disease process. This interaction can lead to immune system dysregulation and chronic inflammation.
The IL-23/IL-17 signaling pathway is central to the inflammation seen in AS. Genetic variations can lead to an overactive immune response, where immune cells mistakenly attack healthy tissues.
HLA-B27 may contribute to AS by presenting specific “arthritogenic” peptides, or through abnormal protein folding that causes cellular stress. Chronic inflammation in AS particularly affects the entheses, which are the points where tendons and ligaments attach to bone. This inflammation can cause initial bone erosion, followed by new bone formation, leading to characteristic syndesmophytes and eventual spinal fusion, known as ankylosis.