Do you see what I MHC?

Two independent SNPs discovered this year, rs2281389 and rs1800795, may indicate that the last decade of inconsistent genome-wide association studies hunting for ways to reduce blood cell transplant failures was not for naught. 

Humans have a lot of genetic variation in the human leukocyte antigen (HLA) and this variation creates a somewhat unique signature on the surface of your cells. Your immune system relies on this signature to distinguish its own cells from foreign invaders, and then to target foreigners for attack. This is a great system when you’re trying to fight off a cold, but a problem when you’re trying to find a donor for an organ or tissue transplant. This is why donor registries screen for similar HLA signatures, to minimize the odds of a conflict. There are immune suppressing drugs that lower the odds of rejection, but these come with their own risks. When you’re in need of an organ or tissue donation, you need your immune system working well to help you, not for it to be suppressed.

Graft versus host disease (GVHD) is when the donated cells recognize the recipient as foreign and begin to attack. This affects up to 80% of patients and is a major cause of transplant failure, early complications and death. In the 2012 paper PMID 22837536 researchers looked for SNPs spanning the Major Histocompatibility Complex (MHC) region which didn’t match between 4,000 donor/recipient pairs who were perfectly matched across the 5 major HLA loci. The most significant SNP found, rs2281389, raised the risk and severity of acute GVHD by about 40%. Curiously, it’s the mismatch itself - not any of the possible genotypes - that increases GVHD risk.

Outside the MHC, an independent comprehensive study (PMID 22282500) of 1300 allogeneic hematopoietic cell transplantation (HCT) donors and recipients using previously reported GVHD-associated SNPs concluded that the best replicating - and almost only - variant was IL6 gene SNP rs1800795. This SNP was associated with a 20%-50% increased risk for GVHD, and here, there may be a biological explanation since the rs1800795(G) allele has been associated with increased serum levels of IL-6 and several autoimmune and inflammatory diseases.

Upcoming clinical trials will determine if using these SNPs for improved genetic matching of donors and recipients will lower the incidence of GVHD. And when full genome sequence becomes a routine part of one’s medical record, these type of studies, along with the predictive HLA-typing, will greatly increase the number of potential donors while minimizing rejection risks. As with many Christmas gifts, the new ones will complement and co-exist with the old ones.