Researchers Create Unique Catalog of Diseases Linked to Immune System Gene Variations

Generated by a study by researchers with the University of Arizona College of Pharmacy and Vanderbilt University Medical Center, the catalog could help identify individuals who are at risk for autoimmune diseases, such as type 1 diabetes or rheumatoid arthritis.

The first comprehensive catalog of diseases associated with variations in human leukocyte antigen (HLA) genes in a single population has been created as a result of a study by researchers with the University of Arizona College of Pharmacy and Vanderbilt University Medical Center (VUMC). The catalog could help identify individuals at risk for certain autoimmune diseases, such as type 1 diabetes or rheumatoid arthritis.

HLAs are proteins expressed on the surfaces of cells that enable the immune system to distinguish the body’s own proteins from proteins made by foreign invaders, such as viruses and bacteria. Individual variations in HLA genes have been linked to autoimmune diseases, in which the immune system mistakes normal tissue for a foreign invader and attacks it, as well as with adverse drug reactions and rejection of transplanted organs. People with certain HLA variants may generate antibodies that attack their own tissues in response to an infection, for example. This suggests that in high-risk people some autoimmune diseases could be prevented by identifying and treating infections.

The study, published in the May 10 issue of the journal Science Translational Medicine, confirmed a slew of previously described associations and identified some potential new associations. “In one fell swoop we essentially replicated decades of research on autoimmune associations with the HLA,” said Jason H. Karnes, PharmD, PhD, assistant professor in the UA College of Pharmacy. Dr. Karnes contributed to the study and is co-first author of the paper with Lisa Bastarache, MS, lead data scientist in the Vanderbilt Center for Precision Medicine.

The catalog has been published online at for researchers who want to follow up on the initial discoveries. “To my knowledge no other investigations have made this level of data available” to the wider research community, said Dr. Karnes.

Prior studies typically have studied only one or a few diseases at a time. This comprehensive catalog provides the first opportunity to study many diseases at once, showing that many HLA types affect multiple diseases but in different ways. For example, some HLA types place a person at risk for both type 1 diabetes and rheumatoid arthritis, while others place one at risk for type 1 diabetes but protected against rheumatoid arthritis.

The study also supports the power of electronic health records (EHRs) to advance understanding, treatment and, ultimately, prevention of disease, said senior author Joshua C. Denny, MD, MS, professor of biomedical informatics and medicine at Vanderbilt.

Previous studies have identified associations between the HLA system and individual “phenotypes,” including autoimmune and other diseases, symptoms and other characteristics. The current investigation – called a “phenome-wide association study” or PheWAS – scanned patients’ entire “phenome” of all health characteristics, as noted in the EHR.

The study was made possible by DNA databases maintained at VUMC and the Marshfield Clinic Personalized Medicine Research Project in Marshfield, Wis. To date, more than 230,000 samples from different individuals have been stored in BioVU, Vanderbilt’s massive DNA database. Genetic samples are linked to the corresponding EHRs in which identifying information has been deleted to protect patient privacy. From the genetic code, the researchers inferred which HLAs would be expected to be expressed in nearly 29,000 individuals whose DNA samples were stored in BioVU and another 8,400 samples provided by Scott J. Hebbring, PhD, and colleagues from the Marshfield Clinic. The EHRs from these individuals were screened for the presence of nearly 1,400 different phenotypes that could be linked to the HLA genes.

Type 1 diabetes was the strongest previously described HLA association confirmed by the study but the researchers also found evidence for several new potential associations with multiple sclerosis and cervical cancer. The latter is known to be driven by a viral infection.

“Just imagine what we’ll be able to do with a million people,” said Dr. Denny. “That will produce truly comprehensive catalogs of all these kinds of associations across HLA and everything else. The detail with which we’ll be able to resolve these questions will be staggering.”

Pictured: Jason H. Karnes, PharmD, PhD

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