To investigate this question, McCarroll and his colleagues analyzed a set of commonly deleted genes in roughly 1,300 donor-recipient pairs who were HLA-identical siblings. These samples are part of collections maintained by researchers at Helsinki University, Dana-Farber Cancer Institute, Fred Hutchinson Cancer Research Center, and other institutions.
"There is a handful of places where physician-scientists had the vision to collect these DNA samples over a long period of time," said McCarroll. "That vision has made projects like this one possible."
The DNA analyses zeroed in on a particular gene called UGT2B17. The researchers found that the mismatch that occurs when the gene is absent from donor DNA yet present in recipient DNA is associated with a greater risk of acute GVHD, which arises within 100 days after bone marrow transplantation. At one hospital, the odds of developing the disease were about 1 in 6 among HLA-identical siblings without the gene mismatch, but were about 2 in 5 - a roughly 2.5-fold increase - among HLA-identical siblings with the UGT2B17 mismatch. The researchers observed similar patterns among patients at other hospitals.
Beyond genetics, additional lines of evidence also point to a role for UGT2B17 in GVHD. Data from the Nature Genetics study as well as previous independent studies collectively indicate that distinct branches of the immune system recognize parts of the protein encoded by the UGT2B17 gene, providing tangible proof that it is targeted by the immune system in patients.
The exact features of this gene that may help stoke the immune system in transplant patients are not yet fully clear. But there are some intriguing hints, McCarroll notes. First, the protein encoded by the gene is large, more than 500 amino acids long. In general, the longer a protein, the more opportunities for the immune system to "see" it. The protein also resides on the surface of cells, a prime spot for detection by antibodies, which are part of the immune system's first responders.
Most important, the UGT2B17 protein is abundant in the same tissues that are targeted by immune cells in acute GVHD (liver, intestine and skin), indicating that it is in the right place at the right time.
McCarroll cautions that it is still too early to know whether analyses of this gene should be incorporated into the suite of clinical tests that are run in order to match potential bone marrow donors and recipients. "The two important steps are to see this result broadly replicated in the field, and to precisely measure its effect size, so that clinical scientists can decide whether to include this among the established criteria that are used to find the ideal donor for each patient," he said.
Source: Broad Institute of MIT and Harvard