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Does a ‘genetic collision’ explain kidney transplant failures?
NEW YORK—Research coming of out Columbia University suggests that a “genomic collision” could explain why many kidney transplants fail, even when donors and recipients are thought to be well matched. As researchers in the university’s Vagelos College of Physicians and Surgeons explain, this genomic collision is a genetic incompatibility between kidney donor and recipient, causing the recipient to mount an immune attack against the donor protein, writing in the background section of their paper, “In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection.”
For the paper, “Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection,” which was published May 15 in the New England Journal of Medicine, the team performed a two-stage genetic association study of kidney allograft rejection.
“In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor–recipient pairs,” they wrote. “We defined genomic collision as a specific donor–recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses.”
In the discovery cohort, which included 705 recipients, they found a significant association with allograft rejection at the LIMS1 locus represented by rs893403. This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs. In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype. Wrote the researchers: “We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses.”
Put slightly less technically, in the words of the university’s news release about the publication, a successful organ transplant depends in large part on assuring genetic compatibility between donor and recipient. This is done by matching the donor and recipient’s human leukocyte antigens (HLAs)—cell surface proteins that help the immune system determine which cells are foreign—as closely as possible.
But HLA mismatches can explain only about two-thirds of transplants that fail for immunological reasons. “The rest of those failures are probably due to less common antigens, or so-called minor histocompatibility antigens. However, the identity of most of these antigens and how they lead to rejection is largely not known,” says co-senior author Dr. Krzysztof Kiryluk, the Herbert Irving Assistant Professor of Medicine at Columbia University Vagelos College of Physicians of Surgeons.
The researchers hypothesized that a person whose genome carries a kidney gene with a deleted section might be especially sensitive to organs from a donor whose genome carries the full-sized gene. “The recipient would then be exposed to a protein their immune system would sense as foreign,” said Kiryluk.
The study found that kidney recipients with two copies of a deletion near a gene called LIMS1 had a significantly higher risk of rejection when the donor kidney had at least one full-sized version of the same gene. The risk of rejection was 63% higher among the donor-recipient pairs with this genomic collision, compared to those without this mismatch. “To put this into perspective, the risk of rejection from LIMS1 mismatch is roughly three times as high as the risk due to a single allele mismatch in the HLA,” Kiryluk explained.
Kidney transplant recipients with two copies of the deletion who developed rejection had detectable levels of anti-LIMS1 antibodies in their blood—further evidence that this genomic collision contributes to rejection.
“The exact mechanism by which this deletion exerts its effects is unknown,” says Kiryluk. “It’s likely that it reduces the amount of LIMS1 protein produced, since we find that individuals with two copies of the deletion have lower levels of LIMS1 gene transcript in their kidneys. When these individuals are exposed to a high level of LIMS1 protein in a newly transplanted organ, their immune system is more likely to recognize the LIMS1 antigen as foreign, resulting in rejection.”
“This project illustrates how genetic analysis is empowering clinical care by enabling better matching, and the antibody test potentially presents a noninvasive method for screening for organ rejection in individuals with an existing transplant,” added co-senior author Dr. Ali G. Gharavi, a professor of medicine at the Vagelos College of Physicians and Surgeons.