@Lachezar Stamenov - You are most welcome! I found I had a lot of questions but not a lot of understandable answers for patients on the web. Glad it's helping!

@Helen Cole - This question sent me down a research rabbit hole because it gets asked so often. The answer is a bit dense with genetic terminology, but here's a run down. I'll probably add a chapter about this specifically. While HLA-B27 is the single strongest genetic factor for Ankylosing Spondylitis (AS), the disease is polygenic. Genome-wide association studies (GWAS) have identified over 100 other genetic loci that contribute to AS. Crucially, the genetic landscape of AS varies dramatically depending on a patient's race and geographic origin. Different populations rely on completely different genes and pathways to reach the "threshold" for disease. Here are the other major genes and population-specific genetic links involved in AS: 1. Alternative HLA (MHC) Genes In patients who are HLA-B27 negative, or in populations where HLA-B27 is rare, other HLA genes take over as the primary drivers of the disease: - HLA-B60 (also known as HLA-B*40:01): This is the second most validated HLA association after HLA-B27 and is found in both European and East Asian populations. In Taiwanese populations, research shows a massive "synergistic" interaction; carrying both HLA-B27 and HLA-B60 increases the risk of AS exponentially more than carrying either gene alone. - HLA-B14 (specifically HLA-B*14:03): In sub-Saharan African populations (such as in Togo and Cameroon), HLA-B27 is almost non-existent. In these populations, HLA-B*14:03 is the primary genetic allotype associated with AS. - Other HLA Alleles: Genes such as HLA-B39, HLA-B15, HLA-B7, and HLA-A*02:01 have also been linked to AS susceptibility across various global cohorts. 2. Antigen Processing Genes (The ERAP Family) The way cells process and present proteins to the immune system is a major genetic factor in AS. - ERAP1: This is the second strongest genetic risk factor for AS overall, accounting for about 25% of the genetic risk. However, it has a unique "epistatic" interaction: ERAP1 is only a risk factor for people who are already HLA-B27 positive. ERAP1 trims peptides before they are presented to the immune system; specific variants of this gene are thought to cut peptides to the wrong length, fueling the autoimmune response. - ERAP2: Conversely, variants in the ERAP2 gene have been shown to be strongly associated with AS in HLA-B27-negative patients.