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Researchers may have discovered that a “genetic collision” may be the reason that one-third of all kidney transplants fail for reasons beyond human leukocyte antigen (HLAs) mismatches. Screening more than 700 kidney transplant patients, they found that recipients with a specific single nucleotide polymorphism (SNP) (rs893403) at chromosome 2q12.3 and mostly likely involving a deletion in the LIMS1 gene were more likely to reject kidneys from donors who had at least one normal variant at this locus. Indeed, the risk of rejection in donor-recipient pairs with this collision was nearly 60% higher than the risk among donor–recipient pairs with noncollision genotypes and is equivalent to a mismatch of three of six HLA alleles, according to the researchers.

HLA mismatches account for about two-thirds of immune-related rejections. “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,” said Krzysztof Kiryluk, MD, an assistant professor of medicine at Columbia University’s Vagelos College of Physicians of Surgeons, and co-senior author of the study, which was published in the New England Journal of Medicine.

Kiryluk and his colleagues sought to explore a hypothesis: Individuals carrying the deleted gene sections might be more sensitive to organs from individuals who don’t have this deletion. Because an individual with SNP involving a deletion isn’t normally exposed to the protein product of that gene, it will not develop tolerance to this protein or its missing domain, Kiryluk told CLN Stat. “In this setting, the transplantation of an organ that carries a full-size gene (i.e. the organ expresses the missing protein or protein domain) into an individual who carries the deletion in homozygosity (two copies missing) would result in an immune reaction against this protein.” Put another way, those born without this protein won’t recognize it as “self,” but rather as “foreign,” and can mount an immune attack targeting the protein, he added.

Researchers conducted their study in two phases, screening 705 kidney transplant recipients at Columbia University Irving Medical Center for deletions in 50 common kidney genes that showed up as full-sized genes in the donor. In a follow-up step, they confirmed deletions associated with rejection in 2,004 donor-recipient pairs from three separate European transplant cohorts.

They discovered that recipients harboring two copies of a deletion near the LIMS1 gene had a much greater chance of rejecting the donor kidney with at least one normal variant of this gene. Low oxygenation appeared to exacerbate this type of genetic incompatibility. “In cells that produce LIMS1, the researchers found that low oxygen levels increase LIMS1 production on the cell surface, which may increase the risk of an immune attack,” according to a statement issued by Columbia University Irving Medical Center.

The findings indicate that pretransplant genetic testing of recipients and donors might improve organ matching, Kiryluk said. “The detection of anti-LIMS1 antibodies may also represent a valuable diagnostic test for post-transplant surveillance and early detection of patients at risk of rejection.”

The researchers’ next steps involve validating these findings in studies with larger and more diverse cohorts of transplant patients. “We are also interested in testing if the same genetic incompatibility plays a role in the setting of non-kidney transplants, such as lung or heart transplants. Lastly, we also want to understand the precise mechanism that leads to the development of anti-LIMS1 antibodies in genetically mismatched donor-recipient pairs,” Kiryluk said.