Autoimmune diseases arise when the immune system mistakenly attacks the body’s own tissues, and understanding why certain individuals are predisposed to these conditions has been a central challenge in immunology and precision medicine. Human leukocyte antigens, known as HLA genes, are among the most important regulators of immune response, and variations in these genes have long been suspected to influence risk across a wide range of autoimmune diseases. Researchers at Vanderbilt University Medical Center and the University of Arizona College of Pharmacy have now created the first comprehensive disease catalog linking HLA gene variants to health conditions at a population scale, a resource that could transform how physicians identify and manage autoimmune disease risk.
What HLA Genes Have to Do With Autoimmune Diseases
HLA proteins are expressed on the surface of cells and function like molecular identification tags, enabling the immune system to distinguish the body’s own tissues from foreign invaders such as bacteria and viruses. When this recognition system works correctly, the immune system targets pathogens while leaving healthy tissue alone. When HLA gene variations disrupt this process, the immune system can become confused, generating antibodies that attack normal tissues and triggering autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.
Individual HLA gene variants have also been linked to adverse drug reactions and organ transplant rejection, making them clinically relevant across a wide range of medical contexts beyond autoimmunity. The challenge has been that previous research typically examined these associations one disease at a time, making it impossible to see the full picture of how different HLA variants relate to multiple conditions simultaneously.
How the Autoimmune Disease Catalog Was Built
The study, published in Science Translational Medicine, used a phenome wide association study approach, known as PheWAS, to scan patients’ entire phenome of health characteristics as documented in electronic health records. This allowed the researchers to examine nearly 1,400 different phenotypes across nearly 37,000 individuals whose DNA samples were stored in BioVU, Vanderbilt’s DNA database, as well as samples provided by the Marshfield Clinic Personalized Medicine Research Project in Wisconsin.
From the genetic data, the team inferred which HLA proteins would be expressed in each individual, then cross referenced those inferences against the health records to identify associations between specific HLA variants and hundreds of conditions. The resulting catalog confirmed a large number of previously described autoimmune disease associations and identified several potential new ones, including connections to multiple sclerosis and cervical cancer.
What the Catalog Reveals About Autoimmune Disease Risk
One of the most important insights from the catalog is that many HLA variants affect multiple autoimmune diseases simultaneously, but not always in the same direction. Some HLA types increase risk for both type 1 diabetes and rheumatoid arthritis. Others increase risk for type 1 diabetes while actually providing protection against rheumatoid arthritis. This complex pattern of overlapping and sometimes opposing associations would have been invisible in studies examining only one or a handful of diseases at a time.
The catalog also supports a hypothesis with significant preventive implications. Some autoimmune diseases may be triggered when individuals with certain HLA variants encounter specific infections, generating an antibody response that subsequently attacks their own tissues. If that mechanism can be confirmed, it could open a pathway to prevention: identifying high risk individuals based on their HLA profile and then treating co infections before they trigger autoimmune disease.
The Future of Autoimmune Disease Research Through Precision Medicine
Senior author Joshua Denny, MD, MS, professor of Biomedical Informatics and Medicine at Vanderbilt, directs the Data and Research Center of the federal All of Us Research Program, which aims to enroll one million or more Americans in a landmark study of genetic, environmental, and lifestyle factors affecting health. Denny expressed confidence that this scale of data collection will enable far more detailed resolution of HLA autoimmune disease associations than is currently possible.
The researchers published the disease catalog publicly at phewascatalog.org, making it available to the broader research community. Co first author Jason Karnes noted that no prior investigation had made this level of data accessible at scale, and the hope is that the catalog will serve as a foundation for future research connecting HLA genetics to autoimmune disease prevention and treatment.
To read more about immunology and genetic research, visit the FOMAT blog. FOMAT conducts clinical trials across multiple therapeutic areas including autoimmune and inflammatory diseases. To learn more about active studies, visit FOMAT’s patient studies page.
For the full source, see the original article at DDDmag.com.