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June 4, 2019
Gene deletion raises risk of kidney transplant rejection
At a Glance
- Researchers found that kidney transplant recipients with two copies of a certain DNA sequence deletion had an increased risk of transplant rejection.
- This risk was highest when they received a kidney from a donor who had one or more copies of the intact sequence.
- Such genetic mismatches could potentially be used to screen for likely transplant rejections.
A kidney transplant can greatly improve quality of life for people with kidney failure. But about 20% of donated kidneys are attacked and destroyed by the recipient’s immune system. Transplant rejection can happen despite daily treatments that suppress the immune system.
To help prevent rejection, doctors try to ensure that the recipient and donor are a good genetic match. This includes measuring a group of proteins found on the body’s cells called human leukocyte antigens (HLAs). HLAs help the immune system tell which cells belong to the body and which might belong to foreign invaders, such as bacteria.
The more HLAs that match between a kidney donor and recipient, the more likely a transplant is to be successful. But even a kidney perfectly matched by HLAs can be rejected. This has led scientists to look for other proteins that might drive rejection.
A research team led by Drs. Ali Gharavi and Krzysztof Kiryluk from Columbia University proposed that common gene deletions might play a role in transplant rejection. Common gene deletions often have no obvious effects. But if a person with a deleted portion of a gene received a kidney from someone with at least one intact copy of that gene, the recipient’s immune system might see the protein produced by that gene as foreign.
To test this idea, the researchers measured the frequency of 50 known gene deletions in kidney donors and recipients from around the world. They next looked to see if deletions in any of the genes altered the risk of rejection. The study was funded in part by NIH’s National Center for Advancing Translational Sciences (NCATS) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Results were published on May 16, 2019, in the New England Journal of Medicine.
The researchers first scanned for the 50 common deletions in DNA samples taken from 705 kidney transplant recipients at their hospital. They found that people with a deletion near a gene called LIMS1 had more than an 80% higher risk of rejection than people with at least one intact copy of the gene.
The team next analyzed more than 2,000 donor-recipient pairs. They found that people with the deletion near LIMS1 who received a kidney from a donor with at least one intact gene had a 58% higher risk of rejection than people without this genetic mismatch.
The researchers then tested blood sera from 300 transplant recipients. They found antibodies targeting LIMS1 in all the recipients with the gene deletion who’d experienced transplant rejection. These antibodies weren’t found in the other recipients.
The LIMS1 deletion is absent in people of East Asian ancestry but common in people of European and African descent. The researchers estimated that a genetic mismatch in LIMS1 could occur in up to 15% of transplants from unrelated donors in these groups.
“LIMS1 mismatches could be avoided by pre-transplant genetic screening,” Kiryluk says. “But first we need to validate our findings in larger studies.”
—by Sharon Reynolds
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References: Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection. Steers NJ, Li Y, Drace Z, D'Addario JA, Fischman C, Liu L, Xu K, Na YJ, Neugut YD, Zhang JY, Sterken R, Balderes O, Bradbury D, Ozturk N, Ozay F, Goswami S, Mehl K, Wold J, Jelloul FZ, Rohanizadegan M, Gillies CE, Vasilescu EM, Vlad G, Ko YA, Mohan S, Radhakrishnan J, Cohen DJ, Ratner LE, Scolari F, Susztak K, Sampson MG, Deaglio S, Caliskan Y, Barasch J, Courtney AE, Maxwell AP, McKnight AJ, Ionita-Laza I, Bakker SJL, Snieder H, de Borst MH, D'Agati V, Amoroso A, Gharavi AG, Kiryluk K. N Engl J Med. 2019 May 16;380(20):1918-1928. doi: 10.1056/NEJMoa1803731. PMID: 31091373.
Funding: NIH’s National Center for Advancing Translational Sciences (NCATS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Cancer Institute (NCI), and Office of the Director (OD); Columbia University Transplant Center; New York State Empire Clinical Research Investigator Program; Dean of the Vagelos College of Physicians and Surgeons at Columbia University; Italian Ministry of Education.