Gene UGT2B17 – Major Contributor To Bone Marrow Transplant Success Rate

NewsOn December 4, 2009 at 4:04 am

A generally heritable gene erasure could raise the probability of immune complications subsequent to bone marrow transplantation, a global team of scientists reported in the 22nd November advance online issue of the journal ‘Nature Genetics’. When the gene known as UGT2B17 is absent in the donor’s genome, but there in the receiver’s genome, transplants have a radically increased risk of grave side effect called the graft-versus-host disease wherein the immune cells present in the donor lays assault on the tissues present in the receiver.

bone marrow transplantSteven McCarroll, first author cum asst. Professor from Harvard Medical School, an associate member from the Broad Institute of MIT and Harvard who directed the study when functioning as a postdoctoral member with David Altshuler in Masachusetts General Hospital and the Broad stated that this discovery offers all a peek into the genetic incongruity that could lead to complications subsequent to transplants. He explicated that there are possibly several other compatibility loci still to be uncovered and with improved competence for investigating human heritable variation, it would turn out to become progressively more practicable to spot them.

The basic principle for organ and tissue transplantation is straightforward – removal of the sickly part from a patient and replacing it with a normal complement from a donor. However, there are many aspects of the process that are far from simplistic, inclusive of the heritable incompatibilities that could occur in between the donor and the host tissues. GVHD or graft-versus-host-disease is an immune-associated condition that could crop up as a consequence of such heritable incompatibilities.

GVHD is a prevalent yet grave complication of bone marrow transplantation (additionally called as ‘hemotopoietic stem cell transplantation’) – a method wherein the blood and the immune ‘stem cells’ are separated from a normal individual’s marrow and transplanted to a receiver having a life-menacing ailment, mostly cancers inflicting the blood or the immune system. As a consequence of the transplant, there is reconstitution of the blood and the immune ‘stem cells’ from the donor into the receiver’s body, thus aiding to treat the aberrant ailment. At times, immune cells from the donor identify unknown proteins in their novel host and lay assault on the receiver’s tissues leading to GVHD.

However, not startlingly, GVHD nearly never happens when transplants are done among identical twins that are carrying the similar DNA all through their genomes. Yet, it recurrently crops up after transplants in between siblings that are hereditarily alike although not identical, in spite of them sharing matching DNA in a key location of the genome called as the HLA.

The HLA region is familiar for its part in ascertaining tissue matching, and particular components of it are regularly checked in both the donors and the receivers (called as ‘HLA-matching’) to estimate if an appropriate match could be done. Yet what is unknown is which locations elsewhere in the genome could additionally impact the success rates of organ transplants.

Some years back, McCarroll and his associates, along with other researchers functioning autonomously made the captivating examination that persons could be lacking fairly big pieces of the genome – mostly entailing complete genes – and that this form of heritable variation is prevalent in the human populace. This translates to the fact that an individual could accede to the similar gene erasure from both parents and hence be lacking the gene in its entirety.

The facts that such erasures are prevalent in the human populaces indicate that they have long been there from times immemorial and that the set genes were not decisive to our antecedents.

The thought was that in case an individual is short of a particular gene, his/her immune system has probably never learnt the ways to acknowledge or endure that gene’s parallel protein. In case his/her immune system by chance located the protein – as it could following a bone marrow transplant – the protein would be observed as alien, hence increasing the likelihood of immune complications.

James Bradner, one of the authors of the study who regularly conducts bone marrow transplants as a branch of his clinical job as an oncologist, perceived that there was a significant pattern for this absent genes suggesting something known as ‘sex mismatch’.

Bradner stated it has been apparent for a while now that bone marrow transplants that involve a female donor and a male recipient have a greater risk of developing GVHD. This form of ‘sex mismatch’ occurs due to genes that are carted on the male-specific Y chromosome and are hence present in the male gender and not among females. It appears conceivable that gene erasures elsewhere in the genome could create analogous outcome.

To inspect this query, McCarroll and his associates examined a group of frequently deleted genes in approximately 1,300 donor-recipient pairs that were HLA-identical siblings. Such samples are components of collections that are preserved by scientists from Helsinki University, Dana-Farber Cancer Institute, Fred Hutchinson Cancer Research Center and other institutes.

McCarroll stated that there are limited locations where doctors-researchers had the visualization to gather such DNA samples over protracted periods of time. The analysis of the DNA zeroed in on a certain gene known as UGT2B17. The scientists detected that the mismatch that happens when the gene is missing from donor DNA but present in the receiver DNA is related to a higher risk of acute GVHD that crops up within hundred days subsequent to bone marrow transplantation.

In one hospital, the odds of the ailment developing was seen at one in six amongst HLA-identical siblings with no gene mismatch, however were nearly two in five – an approximate 2.5 fold rise – in HLA-identical siblings having the UGT2B17 mismatch. The scientists noticed analogous patterns in patients in other hospitals.

McCarroll noted that the precise features of this gene that could aid in stoking the immune system among transplant patients are still not totally apparent. Though there are few interesting clues, foremost being the protein encoded by the gene is big, greater than five hundred amino acids long. Hence, the more the length of the protein, greater are the chances for the immune system of noticing it. The protein additionally dwells on the surface of cells, a key location for spotting by antibodies that are part of the immune system’s foremost responders.

Most significantly, the UGT2B17 protein is copious in the similar tissues that are aimed at by the immune cells in acute GVHD (liver, intestines and skin), pointing out that it is in the apt location at the apt time.

McCarroll points out that it is yet too early for deciphering if analyses of this gene must be integrated into the group of clinical tests that are conducted for matching potential bone marrow donors and receivers.

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