Ankylosing Spondylitis (AS) is a chronic inflammatory form of arthritis that primarily targets the spine and the sacroiliac joints, where the spine connects to the pelvis. This inflammation causes pain and stiffness, potentially leading to new bone formation that can fuse sections of the vertebrae. AS has one of the strongest genetic associations of any common human disease. However, developing the condition is the result of a complex interplay between inherited genetic code and external environmental factors.
The Primary Genetic Marker: HLA-B27
The strongest and most widely studied genetic factor linked to Ankylosing Spondylitis is the Human Leukocyte Antigen B27 (HLA-B27). This gene is part of the HLA complex, which provides instructions for making proteins fundamental to the function of the immune system. These proteins sit on the cell surface and present small protein pieces, or peptides, to T-cells to help distinguish between the body’s own cells and foreign invaders.
Approximately 80 to 95 percent of individuals diagnosed with AS carry the HLA-B27 gene variant. Despite this strong statistical link, the gene alone is not sufficient to cause the disease. HLA-B27 is present in roughly 7 to 8 percent of the general population, yet most carriers remain healthy. Only about one to ten percent of people who possess the HLA-B27 gene ever develop Ankylosing Spondylitis, highlighting that it acts as a susceptibility factor requiring combination with other elements to initiate the disease.
Beyond HLA-B27: The Polygenic Landscape
While HLA-B27 accounts for the largest portion of the genetic risk, it explains less than 30 percent of the total inherited tendency to develop AS, indicating a complex polygenic inheritance pattern. Researchers have identified over 100 other genetic regions, or loci, that contribute to susceptibility. These non-HLA genes individually have a small effect but collectively increase the likelihood of disease.
Many of these additional genes regulate the inflammatory processes of the immune system. For instance, two consistently associated non-HLA genes are ERAP1 and IL23R. ERAP1 is an enzyme that affects the peptides displayed by HLA-B27 to T-cells, while IL23R is involved in the signaling pathway of interleukin-23, a protein that promotes inflammation. The discovery of these smaller-effect genes helps explain why some individuals who test negative for HLA-B27 can still develop AS, as their disease may be driven by a unique combination of these other genetic variants.
Genetic Predisposition and Environmental Triggers
The onset of Ankylosing Spondylitis is best understood through the “two-hit” theory, requiring collaboration between genetic susceptibility and external triggers. Inherited genes, particularly HLA-B27 and other variants, establish immune vulnerability. A second, environmental factor is typically required to activate the inflammatory cascade, causing the predisposed immune system to malfunction and target the body’s own tissues.
The role of the gut microbiome, the community of bacteria in the digestive tract, is a prominent area of investigation. Imbalances in gut flora or specific intestinal infections may serve as the environmental “second hit” that initiates inflammation. Another mechanism involves the HLA-B27 protein misfolding and aggregating on the cell surface, which is highly pro-inflammatory. This misfolding triggers a stress response that activates immune pathways, especially when combined with an environmental challenge. Lifestyle factors such as smoking have also been implicated as environmental modifiers, potentially worsening disease activity in those susceptible to AS.
Understanding Inheritance Risk for Family Members
The high heritability of Ankylosing Spondylitis results in a significantly elevated risk for first-degree relatives (siblings, parents, and children). While the risk of developing AS for the general population is low (estimated between 0.1 and 0.8 percent), this risk increases dramatically for close family members of an affected individual.
First-degree relatives are approximately 10 to 20 times more likely to develop AS than someone with no family history. For children of an affected parent, the risk is estimated to be 4 to 11 percent. Even if a child inherits the HLA-B27 gene, the likelihood of them expressing the disease (penetrance) remains low, with only 5 to 10 percent of HLA-B27 positive children developing the condition. This low penetrance underscores that the genetic component is a strong risk factor, but it is not deterministic.