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Vanderbilt University Medical Center (VUMC) and the University of Arizona College of Pharmacy researchers have generated a first-of-its-kind comprehensive catalog of diseases associated with variations in human leukocyte antigen (HLA) genes that regulate the body's immune system.

The report, published in the journal Science Translational Medicine, confirmed a broad selection 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 Karnes, Ph.D., Pharm.D., co-first author of the paper.

The catalog could help identify individuals who are at risk for certain autoimmune diseases, or who may generate antibodies that attack their own tissues in response to an infection.

HLAs are proteins expressed on the surfaces of cells that play a key role in immune response by singalling “self” tissues from “nonself” tissues such as invading pathogens. Individual variations in HLA genes also have been linked to adverse drug reactions, rejection of transplanted organs and autoimmune diseases including type 1 diabetes and rheumatoid arthritis, in which the immune system mistakes normal tissue for a foreign invader and attacks it.

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

Prior studies have typically studied only one or a handful of diseases at a time. By studying many diseases at once, this study was able to show 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 are risk factors for type 1 diabetes but protect against rheumatoid arthritis.

The study was made possible by DNA databases maintained at VUMC and the Marshfield Clinic Personalized Medicine Research Project in Marshfield, Wisconsin.

To date, more than 230,000 samples from different individuals have been stored in BioVU, Vanderbilt's massive DNA database. To help link the samples to phenotypic information for the study, 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 Hebbring, Ph.D., and colleagues from the Marshfield Clinic.

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.

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