LILRB3 genetic variation is associated with kidney transplant failure in African American recipients

Zeguo Sun^#¹, Zhengzi Yi^#¹, Chengguo Wei^#¹, Wenlin Wang¹, Tianyuan Ren², Paolo Cravedi¹, Fasika Tedla³, Stephen C Ward⁴, Evren Azeloglu¹, Daniel R Schrider⁵, Yun Li⁵, Atlas Khan⁶, Francesca Zanoni⁶, Jia Fu¹, Sumaria Ali⁷, Shun Liu⁸, Deguang Liang⁹, Tong Liu¹⁰, Hong Li¹⁰, Caixia Xi¹, Thi Ha Vy¹, Gohar Mosoyan¹, Quan Sun⁵, Ashwani Kumar¹¹, Zhongyang Zhang¹², Samira Farouk¹, Kirk Campell¹, Jordi Ochando¹³, Kyung Lee¹, Steve Coca¹, Jenny Xiang¹⁴, Patricia Connolly¹⁵, Lorenzo Gallon¹⁶, Philip J O'Connell¹⁷, Robert Colvin¹⁸, Madhav C Menon¹¹, Girish Nadkarni¹, John C He¹, Monica Kraft¹⁹, Xuejun Jiang⁹, Xuewu Zhang⁸, Krzysztof Kiryluk⁶, Aravind Cherukuri²⁰, Fadi G Lakkis²⁰, Weiguo Zhang², Shu-Hsia Chen⁷, Peter S Heeger²¹, Weijia Zhang²²

Affiliations

¹ Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
³ The Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA.
⁷ Center for Immunotherapy Research, Houston Methodist Neal Cancer Center and Houston Methodist Research Institute, Houston, TX, USA.
⁸ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁹ Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Center for Advanced Proteomics Research and Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, Newark, NJ, USA.
¹¹ Department of Medicine, Yale University, New Haven, CT, USA.
¹² Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Microbiology and Immunology, Weil Cornell Medicine, New York, NY, USA.
¹⁵ VericiDx Inc., Franklin, TN, USA.
¹⁶ Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
¹⁷ Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
¹⁸ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁰ Departments of Surgery, Immunology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²¹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²² Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. weijia.zhang@mssm.edu.

^# Contributed equally.

PMID: 40065170
DOI: 10.1038/s41591-025-03568-z

LILRB3 genetic variation is associated with kidney transplant failure in African American recipients

Zeguo Sun et al. Nat Med. 2025 May.

. 2025 May;31(5):1677-1687.

doi: 10.1038/s41591-025-03568-z. Epub 2025 Mar 10.

Authors

Affiliations

¹ Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
² Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
³ The Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Division of Nephrology, Department of Medicine, Columbia University, New York, NY, USA.
⁷ Center for Immunotherapy Research, Houston Methodist Neal Cancer Center and Houston Methodist Research Institute, Houston, TX, USA.
⁸ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁹ Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Center for Advanced Proteomics Research and Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, Newark, NJ, USA.
¹¹ Department of Medicine, Yale University, New Haven, CT, USA.
¹² Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Microbiology and Immunology, Weil Cornell Medicine, New York, NY, USA.
¹⁵ VericiDx Inc., Franklin, TN, USA.
¹⁶ Department of Medicine, University of Illinois Chicago, Chicago, IL, USA.
¹⁷ Centre for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
¹⁸ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁰ Departments of Surgery, Immunology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²¹ Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
²² Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. weijia.zhang@mssm.edu.

^# Contributed equally.

PMID: 40065170
DOI: 10.1038/s41591-025-03568-z

Erratum in

Author Correction: LILRB3 genetic variation is associated with kidney transplant failure in African American recipients.
Sun Z, Yi Z, Wei C, Wang W, Ren T, Cravedi P, Tedla F, Ward SC, Azeloglu E, Schrider DR, Li Y, Khan A, Zanoni F, Fu J, Ali S, Liu S, Liang D, Liu T, Li H, Xi C, Vy TH, Mosoyan G, Sun Q, Kumar A, Zhang Z, Farouk S, Campell K, Ochando J, Lee K, Coca S, Xiang J, Connolly P, Gallon L, O'Connell PJ, Colvin R, Menon MC, Nadkarni G, He JC, Kraft M, Jiang X, Zhang X, Kiryluk K, Cherukuri A, Lakkis FG, Zhang W, Chen SH, Heeger PS, Zhang W. Sun Z, et al. Nat Med. 2025 May;31(5):1712. doi: 10.1038/s41591-025-03706-7. Nat Med. 2025. PMID: 40234733 No abstract available.

Abstract

African American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared with other racial and ethnic populations, highlighting the need to identify causative factors. Here, in the Genomics of Chronic Allograft Rejection cohort, pretransplant blood RNA sequencing revealed a cluster of four consecutive missense single-nucelotide polymorphisms (SNPs), within the leukocyte immunoglobulin-like receptor B3 (LILRB3) gene, strongly associated with death-censored graft loss. This SNP cluster (named LILRB3-4SNPs) encodes missense mutations at amino acids 617-618 proximal to a SHP1/2 phosphatase-binding immunoreceptor tyrosine-based inhibitory motif. The LILRB3-4SNPs cluster is specifically enriched within AA individuals and exhibited a strong association with death-censored graft loss and estimated glomerular filtration rate decline in the AA participants from multiple transplant cohorts. In two large Biobanks (BioMe and All-of-Us), the LILRB3-4SNPs cluster was associated with the early onset of end-stage renal disease and acted synergistically with the apolipoprotein L1 (APOL1) G1/G2 allele to accelerate disease progression. The SNPs were also linked to multiple immune-related diseases in AA individuals. Last, on multiomics analysis of blood and biopsies, recipients with LILRB3-4SNPs showed enhanced inflammation and monocyte ferroptosis. While larger and prospective studies are needed, our data provide insights on the genetic variation underlying kidney transplant outcomes.

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Conflict of interest statement

Competing interests: Weijia Zhang reports personal fees from VericiDx and reports the patents (Patents US Provisional Patent Application F&R ref. 27527-0134P01, serial no. 61/951,651, filed March 2014; Method for identifying kidney allograft recipients at risk for chronic injury; US Provisional Patent Application: Methods for Diagnosing Risk of Renal Allograft Fibrosis and Rejection (miRNA); US Provisional Patent Application: Method for Diagnosing Subclinical Acute Rejection by RNA Sequencing Analysis of a Predictive Gene Set; US Provisional Patent Application: Pretransplant prediction of post- transplant acute rejection). M.C.M. receives research support from Natera. P. Cravedi is a consultant for Chinook therapeutics. L.G. is the non-executive Director and Chair of the science advisory board for Verici. The other investigators have no financial interest to declare.

References

1. Chertow, G. M. & Milford, E. L. Poorer graft survival in African–American transplant recipients cannot be explained by HLA mismatching. Adv. Ren. Replace Ther. 4, 40–45 (1997). - PubMed
1. Ilori, T. O. et al. Racial and ethnic disparities in graft and recipient survival in elderly kidney transplant recipients. J. Am. Geriatr. Soc. 63, 2485–2493 (2015). - PubMed - PMC
1. Ng, F. L., Holt, D. W., Chang, R. W. & Macphee, I. A. Black renal transplant recipients have poorer long-term graft survival than CYP3A5 expressers from other ethnic groups. Nephrol. Dial. Transplant. 25, 628–634 (2010). - PubMed
1. Roy, N. et al. Association of recipient APOL1 kidney risk alleles with kidney transplant outcomes. Transplantation 107, 2575–2580 (2023). - PubMed - PMC
1. Zhang, Z. et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J. Clin. Invest. 131, e146643 (2021). - PubMed - PMC

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LILRB3 genetic variation is associated with kidney transplant failure in African American recipients

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LILRB3 genetic variation is associated with kidney transplant failure in African American recipients

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Erratum in

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