A commonly inherited gene deletion can increase the likelihood of immune complications following bone marrow transplantation, an international team of researchers reports in the November 22 advance online issue of Nature Genetics. When the gene, called UGT2B17, is missing from the donor's genome but present in the recipient's, transplants have a significantly greater risk of a serious side-effect known as graft-versus-host disease, in which immune cells from the donor attack tissues in the recipient.
"This finding gives us a glimpse into the genetic incompatibilities that can complicate transplants," said first author Steven McCarroll, an assistant professor at Harvard Medical School and an associate member of the Broad Institute of MIT and Harvard, who led the study while working as a postdoctoral fellow with David Altshuler at Massachusetts General Hospital and the Broad. "There are likely many other compatibility loci left to be found, and with the enhanced capabilities for surveying human genetic variation, it will become increasingly feasible to find them."
The basic premise behind organ and tissue transplantation is simple: remove the diseased part from one patient and replace it with a healthy counterpart from another. But there are several facets of the process that are anything but simple, including the genetic incompatibilities that can exist between donor and host tissues. Graft-versus-host disease (GVHD) is one immune-related condition that can arise as a result of these genetic mismatches.
GVHD is a common yet serious complication of bone marrow transplantation (also known as "hematopoietic stem cell transplantation"), a procedure in which blood and immune "stem cells" are isolated from a healthy person's marrow and transferred to a patient with a life-threatening disease, often cancers of the blood or immune system. As a result of the transplant, the donor's blood and immune systems are reconstituted in the recipient's body, helping to cure the offending illness. Sometimes, donor immune cells detect unfamiliar proteins in their new host and attack the patient's tissues, causing GVHD.
Not surprisingly, GVHD almost never occurs when transplants involve identical twins, who carry the same DNA throughout their genomes. However, it frequently arises following transplants between siblings who are genetically similar though not identical, even when they share identical DNA in a key region of the genome known as the HLA.
The HLA region is well known for its role in determining tissue compatibility, and certain parts of it are routinely tested in both donors and recipients (known as "HLA-matching") to gauge whether a suitable match can be made. What is not known, however, is which sites elsewhere in the genome might also impact the success of organ transplantation.
A few years ago, McCarroll and his colleagues, as well as other scientists working independently, made the intriguing observation that individuals can be missing relatively large chunks of the genome - often involving entire genes - and that this type of genetic variation is common in the human population. That means that a person could inherit the same gene deletion from both parents and thus lack the gene entirely.
The fact that these deletions are fairly common in human populations suggests that they have been around for tens of thousands of years, and that the encoded genes were not critical to our ancestors.
"We asked, 'Are there situations in which these deleted genes might matter more to us than to our ancestors,'" said McCarroll. "One thing that is part of our world that wasn't part of theirs is transplantation."
The idea was that if a person lacks a certain gene, his immune system has likely never learned to accept or "tolerate" that gene's corresponding protein. If his immune system somehow came across the protein - as it might after a bone marrow transplant - the protein would be perceived as foreign, thereby raising the risk of immune complications.
In exploring this idea, McCarroll teamed up with James Bradner, then a postdoctoral fellow at the Broad Institute, who is now an instructor in medicine at the Dana-Farber Cancer Institute and a Broad Institute associate member. Bradner routinely performs bone marrow transplantation as part of his clinical work as an oncologist, and knew that there was an important precedent for this missing genes idea in something called "sex mismatch."
"It's been clear for some time that bone marrow transplants involving a female donor and a male patient pose a higher risk of GVHD," said Bradner. "This 'sex mismatch' arises from genes that are carried on the male-specific Y chromosome and are therefore present in males but not in females. It seemed plausible that gene deletions elsewhere in the genome could produce a similar consequence."