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Kidney Transplant Rejection Linked to New Mismatch Locus

NEW YORK (GenomeWeb) – A team led by investigators at Columbia University has identified a new form of genetic mismatch, or "genomic collision," between kidney transplant recipients and organ donors that appears to increase the risk of allograft rejection.

In The New England Journal of Medicine, the researchers presented findings from a two-stage association study aimed at uncovering high-priority copy number variants influencing kidney allograft rejection in more than 700 transplant recipients at Columbia's Irving Medical Center. In particular, they focused on the so-called genomic collision situations, in which transplant recipients carried two copies of a deletion that was not homozygous in the organ donor.

With this approach, the team tracked down a significant association between allograft rejection and a chromosome 2 locus that contained LIMS1. The association was subsequently verified in three additional kidney recipient-donor cohorts, while follow-up analyses indicated that allograft rejection may stem, in part, from an uptick in the expression of immunoglobulin IgG2 and IgG3 antibodies targeting the LIMS1 protein product.

"Taken together, our results provide support for genomic collision at chromosome 2q12.3 contributing to the risk of allograft rejection and point to LIMS1 as a potential minor histocompatibility antigen encoded by this locus," co-senior and co-corresponding authors Krzysztof Kiryluk, a nephrology researcher at Columbia, and Ali Gharavi, chief of Columbia's nephrology division, and their colleagues wrote.

"To our knowledge, the LIMS1 locus has not been detected in previous genome-wide association studies of kidney transplant rejection," they added. "We suspect that this is probably due to the limited sample size of earlier studies and to the fact that limited research has been done in testing the genomic-collision model."

A significant proportion of past kidney transplant recipients in the US are back on the transplant wait list due to allograft failure, the team noted. That has prompted searches for new histocompatibility antigens that can prompt dangerous immune responses, beyond factors that are already assessed in donors and recipients such as human leukocyte antigen (HLA) matching.

"[T]he overall incidence of known alloantibodies to minor histocompatibility antigens is low, which suggests that there are contributions from additional antigens," the authors explained. "We hypothesized that the recipient's inheritance of variants that disrupt kidney genes predisposes the recipient to allosensitization and rejection."

With that in mind, the researchers used NimbleGen array-based comparative genome hybridization to search for 50 suspicious deletions affecting protein-coding parts of the genome in 705 kidney transplant recipients. From there, they searched for associations with kidney allograft rejection in a "time-to-event survival analysis" in the patients, who were followed for more than eight-and-a-half years, on average.

That analysis highlighted a variant in LIMS1 on chromosome 2 that was further tied to allograft rejection risk in the team's replication analyses, which followed more than 2,000 kidney transplant recipients from cohorts in Ireland, the Netherlands, or Italy for more than six to nearly 10 years, on average.

From there, the researchers explored the possibility that the association was related to genomic collision events at the locus — mismatches between donors and recipients that prompted an immune reaction to the transplanted organ tissue. Their analysis of all 2,709 transplant recipients from the discovery and validation stages of the study, which included genotypes for more than 2,000 organ donors, propped up this notion.

The team got further evidence for the hypothesis following a functional analysis of the rejection-related risk variant, and seroreactivity experiments that relied on protein array data for hundreds more kidney transplant recipients who did or did not experience allograft rejection.

The authors noted that the LIMS1 protein also appears to be expressed in other commonly transplanted organs, including the heart and lung, though they cautioned that "follow-up studies will be useful in determining whether our findings are generalizable to other organs."