Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the spine and sacroiliac joints, leading to pain and stiffness. Its development is complex, involving multiple genes and various environmental factors. While genetics significantly influence susceptibility, they do not solely determine whether an individual will develop AS.
The Primary Genetic Link: HLA-B27
The human leukocyte antigen B27, or HLA-B27, is a gene that has a strong association with AS. This gene is part of the major histocompatibility complex (MHC) and plays a role in the immune system by helping it distinguish between the body’s own proteins and foreign invaders like viruses and bacteria. HLA-B27 typically binds and presents peptides from inside cells to T cells, which are a type of immune cell.
While HLA-B27 is found in approximately 90% of individuals with AS, its presence alone does not guarantee the development of the condition. Only a small percentage, around 2%, of HLA-B27 positive individuals in the general population will develop AS. Conversely, some people with AS do not have the HLA-B27 gene, indicating that other factors are involved in disease onset. The HLA-B27 gene is thought to contribute to about 20-30% of the total genetic risk for AS.
Beyond HLA-B27: Other Genetic Factors
While HLA-B27 is the most recognized genetic marker, AS is a complex genetic disease with over 100 associated genetic regions, known as loci. Each of these additional genes has a smaller individual effect compared to HLA-B27, but their combined influence accounts for a larger portion of the overall genetic risk.
Many of these “smaller effect” genes are involved in regulating the immune system and inflammatory pathways. Examples include genes related to intracellular antigen processing, such as ERAP1, and cytokine genes involved in pathways like the IL-17 and IL-23 pathways. These genes influence how the body responds to perceived threats and manages inflammation.
The Role of Environment and Gene Interaction
Genetics alone do not fully explain who develops AS; environmental factors also play a significant role. One notable environmental factor is the gut microbiome, which refers to the trillions of microorganisms residing in the human digestive tract.
An imbalance in gut bacteria, known as gut dysbiosis, has been implicated in AS development. Certain bacteria, such as Klebsiella pneumoniae, have been studied for their potential role in triggering inflammation. The “gut-joint axis” theory suggests that microbial antigens from the gut can mistakenly trigger an immune response against spinal tissues, a process called molecular mimicry. The interaction between genes like HLA-B27 and ERAP1, involved in processing peptides for immune presentation, also influences disease susceptibility.
Implications for Family Members
Given the genetic component of AS, there is an increased risk for close relatives of affected individuals. First-degree relatives, such as parents or siblings of someone with AS, have a higher chance of developing the condition. However, it is important to remember that this is an increased risk, not a certainty.
Genetic testing for HLA-B27 can indicate a higher susceptibility to AS, but it is not a diagnostic test for the disease itself. A positive HLA-B27 test in the absence of symptoms does not mean a person will definitely develop AS. If family members experience symptoms like persistent inflammatory back pain, especially if it starts before age 45, seeking early medical evaluation is advisable. Early diagnosis and appropriate management can help control symptoms and potentially slow disease progression.