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

Zeguo Sun; Zhengzi Yi; Chengguo Wei; Wenlin Wang; Tianyuan Ren; Paolo Cravedi; Fasika Tedla; Stephen C. Ward; Evren Azeloglu; Daniel R. Schrider; Yun Li; Atlas Khan; Francesca Zanoni; Jia Fu; Sumaria Ali; Shun Liu; Deguang Liang; Tong Liu; Hong Li; Caixia Xi; Thi Ha Vy; Gohar Mosoyan; Quan Sun; Ashwani Kumar; Zhongyang Zhang; Samira Farouk; Kirk Campell; Jordi Ochando; Kyung Lee; Steve Coca; Jenny Xiang; Patricia Connolly; Lorenzo Gallon; Philip J. O’Connell; Robert Colvin; Madhav C. Menon; Girish Nadkarni; John C. He; Monica Kraft; Xuejun Jiang; Xuewu Zhang; Krzysztof Kiryluk; Aravind Cherukuri; Fadi G. Lakkis; Weiguo Zhang; Shu Hsia Chen; Peter S. Heeger; Weijia Zhang

doi:10.1038/s41591-025-03568-z

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

Zeguo Sun, Zhengzi Yi, Chengguo Wei, Wenlin Wang, Tianyuan Ren, Paolo Cravedi, Fasika Tedla, Stephen C. Ward, Evren Azeloglu, Daniel R. Schrider, Yun Li, Atlas Khan, Francesca Zanoni, Jia Fu, Sumaria Ali, Shun Liu, Deguang Liang, Tong Liu, Hong Li, Caixia XiThi Ha Vy, Gohar Mosoyan, Quan Sun, Ashwani Kumar, Zhongyang Zhang, Samira Farouk, Kirk Campell, Jordi Ochando, Kyung Lee, Steve Coca, Jenny Xiang, Patricia Connolly, Lorenzo Gallon, Philip J. O’Connell, Robert Colvin, Madhav C. Menon, Girish Nadkarni, John C. He, Monica Kraft, Xuejun Jiang, Xuewu Zhang, Krzysztof Kiryluk, Aravind Cherukuri, Fadi G. Lakkis, Weiguo Zhang, Shu Hsia Chen, Peter S. Heeger, Weijia Zhang

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Article number	e146643
Pages (from-to)	1677-1687
Number of pages	11
Journal	Nature Medicine
Volume	31
Issue number	5
DOIs	https://doi.org/10.1038/s41591-025-03568-z
State	Published - May 2025

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1038/s41591-025-03568-z

Cite this

Sun, Z., Yi, Z., Wei, C., Wang, W., Ren, T., Cravedi, P., Tedla, F., Ward, S. C., Azeloglu, E., Schrider, D. R., Li, Y., Khan, A., Zanoni, F., Fu, J., Ali, S., Liu, S., Liang, D., Liu, T., Li, H., ... Zhang, W. (2025). LILRB3 genetic variation is associated with kidney transplant failure in African American recipients. Nature Medicine, 31(5), 1677-1687. Article e146643. https://doi.org/10.1038/s41591-025-03568-z

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 2025, 'LILRB3 genetic variation is associated with kidney transplant failure in African American recipients', Nature Medicine, vol. 31, no. 5, e146643, pp. 1677-1687. https://doi.org/10.1038/s41591-025-03568-z

@article{71910a8d6061445f94f5b89a79cb8a89,

title = "LILRB3 genetic variation is associated with kidney transplant failure in African American recipients",

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.",

author = "Zeguo Sun and Zhengzi Yi and Chengguo Wei and Wenlin Wang and Tianyuan Ren and Paolo Cravedi and Fasika Tedla and Ward, {Stephen C.} and Evren Azeloglu and Schrider, {Daniel R.} and Yun Li and Atlas Khan and Francesca Zanoni and Jia Fu and Sumaria Ali and Shun Liu and Deguang Liang and Tong Liu and Hong Li and Caixia Xi and Vy, {Thi Ha} and Gohar Mosoyan and Quan Sun and Ashwani Kumar and Zhongyang Zhang and Samira Farouk and Kirk Campell and Jordi Ochando and Kyung Lee and Steve Coca and Jenny Xiang and Patricia Connolly and Lorenzo Gallon and O{\textquoteright}Connell, {Philip J.} and Robert Colvin and Menon, {Madhav C.} and Girish Nadkarni and He, {John C.} and Monica Kraft and Xuejun Jiang and Xuewu Zhang and Krzysztof Kiryluk and Aravind Cherukuri and Lakkis, {Fadi G.} and Weiguo Zhang and Chen, {Shu Hsia} and Heeger, {Peter S.} and Weijia Zhang",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.",

year = "2025",

month = may,

doi = "10.1038/s41591-025-03568-z",

language = "English (US)",

volume = "31",

pages = "1677--1687",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "5",

}

TY - JOUR

T1 - LILRB3 genetic variation is associated with kidney transplant failure in African American recipients

AU - Sun, Zeguo

AU - Yi, Zhengzi

AU - Wei, Chengguo

AU - Wang, Wenlin

AU - Ren, Tianyuan

AU - Cravedi, Paolo

AU - Tedla, Fasika

AU - Ward, Stephen C.

AU - Azeloglu, Evren

AU - Schrider, Daniel R.

AU - Li, Yun

AU - Khan, Atlas

AU - Zanoni, Francesca

AU - Fu, Jia

AU - Ali, Sumaria

AU - Liu, Shun

AU - Liang, Deguang

AU - Liu, Tong

AU - Li, Hong

AU - Xi, Caixia

AU - Vy, Thi Ha

AU - Mosoyan, Gohar

AU - Sun, Quan

AU - Kumar, Ashwani

AU - Zhang, Zhongyang

AU - Farouk, Samira

AU - Campell, Kirk

AU - Ochando, Jordi

AU - Lee, Kyung

AU - Coca, Steve

AU - Xiang, Jenny

AU - Connolly, Patricia

AU - Gallon, Lorenzo

AU - O’Connell, Philip J.

AU - Colvin, Robert

AU - Menon, Madhav C.

AU - Nadkarni, Girish

AU - He, John C.

AU - Kraft, Monica

AU - Jiang, Xuejun

AU - Zhang, Xuewu

AU - Kiryluk, Krzysztof

AU - Cherukuri, Aravind

AU - Lakkis, Fadi G.

AU - Zhang, Weiguo

AU - Chen, Shu Hsia

AU - Heeger, Peter S.

AU - Zhang, Weijia

PY - 2025/5

Y1 - 2025/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=86000745799&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=86000745799&partnerID=8YFLogxK

U2 - 10.1038/s41591-025-03568-z

DO - 10.1038/s41591-025-03568-z

M3 - Article

C2 - 40065170

AN - SCOPUS:86000745799

SN - 1078-8956

VL - 31

SP - 1677

EP - 1687

JO - Nature Medicine

JF - Nature Medicine

IS - 5

M1 - e146643

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this