A commonly inherited gene deletion can increase the likelihood of immune complications following bone marrow transplantation, an international research team has reported.
When the gene was missing from the donor’s genome—but present in the recipient’s—transplants had more than twice the risk of graft-versus-host disease (GVHD), a serious side effect in which immune cells from the donor attack tissues in the recipient.
“The donor’s immune system sees the protein for the first time in the transplant recipient, and its unfamiliarity appears to increase the risk of GVHD,” said first author Steven McCarroll, an HMS assistant professor of genetics and associate member of the Broad Institute of MIT and Harvard.
The deletions are a type of genome variant known as copy number variations, which also include repeated and reversed chunks of genome. In the last few years, other specific deletions have been connected to common human diseases and traits, thanks in part to McCarroll, who helped develop technologies that can detect these associations.
Using patient DNA collections established at Dana-Farber Cancer Institute and elsewhere, the team analyzed a set of commonly deleted genes in roughly 1,300 donor–recipient pairs of siblings with identical immune components known as HLA.
The DNA analyses zeroed in on a particular gene called UGT2B17. At one hospital, the odds of GVHD 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 those with the mismatch. The researchers observed similar patterns at other hospitals.
The effect size was similar to the clinically important effect of “sex mismatch,” which arises from immune responses of organs from a female donor in male recipients against proteins encoded on the Y chromosome, said co-author James Bradner, an HMS instructor in medicine at DFCI and a Broad associate member. The findings need to be more broadly replicated and the effect size more precisely measured before the clinical utility of these findings can be assessed.
“One of the nice things about this story is the extent to which it draws on the collective assets of the Harvard community—basic-science and clinical,” said McCarroll, who led the study while working as a postdoctoral fellow with senior author David Altshuler at Massachusetts General Hospital and the Broad. The paper was published online Nov. 22 in Nature Genetics.
Students may contact Steven McCarroll at mccarroll @genetics.med.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts.
Funding Sources: The Broad Institute of MIT and Harvard, the Academy of Finland, the Helsinki University Central Hospital Research Fund, the Fred Hutchinson Cancer Research Center, a Lilly Life Sciences Research fellowship, the S. Juselius Foundation, the Center of Excellence Program of the Finnish Academy and the National Institutes of Health. The authors are solely responsible for the content of this work.
