Genetic polymorphisms of Leukocyte Immunoglobulin-Like Receptor B3 ( LILRB3 ) gene in African American kidney transplant recipients are associated with post-transplant graft failure
Year: 2024
Type: preprint
Study design: Observational Study
Abstract: Background African American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared to other racial and ethnic populations, highlighting the need to identify causative factors underlying this disparity. Method We analyzed RNA sequences of pretransplant whole blood from subjects followed in three kidney transplant cohorts to identify single nucleotide polymorphisms (SNPs) associated with death censored graft loss (DCGL). We employed a meta-analysis to uncover key transcriptional signatures and pathways associated with the identified SNPs and used single cell RNA to define cellular specificity. We characterized SNP functions using in vitro immunological and survival assays and tested for associations between the identified SNPs and other immune-related diseases using a ∼30,100 subject, electronic health record (EHR)-linked database. Results We uncovered a cluster of four consecutive missense SNPs in the Leukocyte Immunoglobulin-Like Receptor B3 ( LILRB3 , a negative immune response regulator) gene that strongly associated with DCGL. This LILRB3 -4SNPs cluster encodes missense mutations at amino acids 617-618 proximal to a SHP-1/2 phosphatase-binding ITIM motif. LILRB3 -4SNPs is specifically enriched within subjects of AA ancestry (8.6% prevalence vs 2.3% in Hispanic and 0.1% in European populations), is not linked to APOL1 G1/G2 alleles, and exhibited a strong association with DCGL. Analysis of PBMC and transplant biopsies from recipients with LILRB3 -4SNPs showed evidence of enhanced adaptive immune responsiveness and ferroptosis-associated death in monocytes. Overexpression of the variant allele in THP-1 cells (macrophage line) induced augmented inflammation and ferroptosis, which were attenuated by a ferroptosis inhibitor, verifying a causal link. The LILRB3 -4SNPs also associated with multiple systemic and organ-specific immune-related diseases in AAs, consistent with conferring a broadly relevant immune function. Conclusion the LILRB3 -4SNPs represent a functionally important, distinct genetic risk factor for kidney transplant outcome and development/severity of other immune-related diseases in patients of AA ancestry. Pharmacological targeting of ferroptosis should be tested to prevent or treat these disease processes in AA recipients carrying LILRB3 -4SNPs.
Authors: Zeguo Sun, Zhengzi Yi, Chengguo Wei, Wenlin Wang, Paolo Cravedi, Fasika Tedla, Stephen C. Ward, Evren Azeloglu, Daniel R. Schrider, Yun Li, Sumaria Ali, Tianyuan Ren, Shun Liu, Deguang Liang, Jia Fu, 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, Patti Connolly, Lorenzo Gallon, Robert Colvin, Madhav Menon, Girish Nadkarni, John C. He, Monica Kraft, Xuejun Jiang, Xuewu Zhang, Weiguo Zhang, Weiguo Zhang, Shu-hsia Chen, Peter Heeger, Weijia Zhang, Weijia Zhang
Institutions: Icahn School of Medicine at Mount Sinai, University of North Carolina at Chapel Hill, Houston Methodist, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou Institute of Systems Medicine, The University of Texas Southwestern Medical Center, Memorial Sloan Kettering Cancer Center, Rutgers, The State University of New Jersey, Yale University, Weill Cornell Medicine, University of Illinois Chicago, Harvard University, Massachusetts General Hospital, Cedars-Sinai Medical Center
Language: English
Subfield: Transplantation
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W4392773764