Mismatches in Gene Deletions and Kidney-related Proteins As Candidates for Histocompatibility Factors in Kidney Transplantation

Overview

Journal Kidney Int Rep

Publisher Elsevier

Specialty Nephrology

Date 2022 Dec 19

PMID 36531875

Authors

Salla Markkinen

Ilkka Helantera

Jouni Lauronen

Marko Lempinen

Jukka Partanen

Kati Hyvarinen

Affiliations

Soon will be listed here.

Abstract

Introduction: The genomic mismatch level between donor and recipient may be associated with the risk of rejection and graft survival. We determined the association of genome-level matching with acute rejection in deceased-donor kidney transplantation.

Methods: The study cohort consists of 1025 recipient-donor pairs transplanted in a single center from 2007 to 2017 in Helsinki. The associations between the sums of whole-genome missense variant mismatches and missense mismatches in transmembrane, secretory, and kidney-related proteins, with acute rejection were estimated using Cox model. In addition, we analyzed 40 deletion-tagging variants using Cox model.

Results: The association analysis between mismatch sums of kidney-related proteins and acute rejection resulted in an unadjusted hazard ratio (HR) of 1.15 (95% confidence interval [CI], 1.01-1.30; = 0.029) and adjusted HR of 1.13 (95% CI, 0.99-1.28; = 0.071). In deletion analysis, a mismatch in rs7542235 genotype GG tagging a homozygous deletion at the complement factor H-related (), proteins locus, predisposed to acute rejection with an unadjusted HR of 3.10 (95% CI, 1.53-6.29; = 0.002) and adjusted HR of 2.97 (95% CI, 1.46-6.05; = 0.003).

Conclusion: In conclusion, analyses of genome-level mismatches may be useful tools in prediction of transplantation outcome. The relative importance differs between populations, because we found evidence for deletion but could not replicate the finding of previously reported deletion.

Citing Articles

Novel Aspects of Immunogenetics and Post-Transplant Events in Kidney Transplantation.

Helantera I, Markkinen S, Partanen J, Hyvarinen K Transpl Int. 2024; 37:13317.

PMID: 39703873 PMC: 11655191. DOI: 10.3389/ti.2024.13317.

Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation.

Nieuwenhuis L, Li Y, Loza B, Lambeck A, Hu S, Gacesa R Hepatol Commun. 2024; 9(1.

PMID: 39670865 PMC: 11637756. DOI: 10.1097/HC9.0000000000000601.

LIM Zinc Finger Domain Containing 1 Risk Genotype of Recipient Is Associated with Renal Tubular Inflammation in Kidney Transplantation.

Caliskan Y, Ozluk Y, Kurashima K, Mirioglu S, Dirim A, Hurdogan O Genes (Basel). 2024; 15(6).

PMID: 38927709 PMC: 11203101. DOI: 10.3390/genes15060773.

Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch.

Cao R, Schladt D, Dorr C, Matas A, Oetting W, Jacobson P PLoS One. 2024; 19(5):e0303446.

PMID: 38820342 PMC: 11142483. DOI: 10.1371/journal.pone.0303446.

Impact of Resolved Preformed, Persistent Preformed, and De Novo Anti-HLA Donor-Specific Antibodies in Kidney Transplant Recipients on Long-Term Renal Graft Outcomes.

Gniewkiewicz M, Czerwinska K, Zielniok K, Durlik M J Clin Med. 2023; 12(10).

PMID: 37240467 PMC: 10219016. DOI: 10.3390/jcm12103361.

References

Stapleton C, Heinzel A, Guan W, van der Most P, van Setten J, Lord G . The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population. Am J Transplant. 2019; 19(8):2262-2273. PMC: 6989089. DOI: 10.1111/ajt.15326. View

Reindl-Schwaighofer R, Heinzel A, Kainz A, van Setten J, Jelencsics K, Hu K . Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohort. Lancet. 2019; 393(10174):910-917. DOI: 10.1016/S0140-6736(18)32473-5. View

Zipfel P, Skerka C . Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009; 9(10):729-40. DOI: 10.1038/nri2620. View

Jozsi M, Licht C, Strobel S, Zipfel S, Richter H, Heinen S . Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood. 2007; 111(3):1512-4. DOI: 10.1182/blood-2007-09-109876. View

Mesnard L, Muthukumar T, Burbach M, Li C, Shang H, Dadhania D . Exome Sequencing and Prediction of Long-Term Kidney Allograft Function. PLoS Comput Biol. 2016; 12(9):e1005088. PMC: 5042552. DOI: 10.1371/journal.pcbi.1005088. View

Cooper J . Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clin J Am Soc Nephrol. 2020; 15(3):430-438. PMC: 7057293. DOI: 10.2215/CJN.11991019. View

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View

Ritari J, Hyvarinen K, Koskela S, Niittyvuopio R, Nihtinen A, Salmenniemi U . Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease After Allogeneic HSCT. Front Immunol. 2019; 10:1625. PMC: 6646417. DOI: 10.3389/fimmu.2019.01625. View

Duquesnoy R, Askar M . HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. V. Eplet matching for HLA-DR, HLA-DQ, and HLA-DP. Hum Immunol. 2007; 68(1):12-25. PMC: 2527859. DOI: 10.1016/j.humimm.2006.10.003. View

10.

Pihlstrom H, Mjoen G, Mucha S, Haraldsen G, Franke A, Jardine A . Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study. Am J Transplant. 2016; 17(2):528-533. DOI: 10.1111/ajt.13995. View

11.

Steers N, Li Y, Drace Z, DAddario J, Fischman C, Liu L . Genomic Mismatch at Locus and Kidney Allograft Rejection. N Engl J Med. 2019; 380(20):1918-1928. PMC: 6589355. DOI: 10.1056/NEJMoa1803731. View

12.

Ghisdal L, Baron C, Lebranchu Y, Viklicky O, Konarikova A, Naesens M . Genome-Wide Association Study of Acute Renal Graft Rejection. Am J Transplant. 2016; 17(1):201-209. PMC: 5215306. DOI: 10.1111/ajt.13912. View

13.

Zhang Z, Menon M, Zhang W, Stahl E, Loza B, Rosales I . Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis. Kidney Int. 2020; 98(3):758-768. PMC: 7483801. DOI: 10.1016/j.kint.2020.04.039. View

14.

Fritsche L, Lauer N, Hartmann A, Stippa S, N Keilhauer C, Oppermann M . An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum Mol Genet. 2010; 19(23):4694-704. DOI: 10.1093/hmg/ddq399. View

15.

Skerka C, Chen Q, Fremeaux-Bacchi V, Roumenina L . Complement factor H related proteins (CFHRs). Mol Immunol. 2013; 56(3):170-80. DOI: 10.1016/j.molimm.2013.06.001. View

16.

McCarroll S, Bradner J, Turpeinen H, Volin L, Martin P, Chilewski S . Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nat Genet. 2009; 41(12):1341-4. PMC: 2804745. DOI: 10.1038/ng.490. View

17.

OBrien R, Phelan P, Conroy J, OKelly P, Green A, Keogan M . A genome-wide association study of recipient genotype and medium-term kidney allograft function. Clin Transplant. 2013; 27(3):379-87. DOI: 10.1111/ctr.12093. View

18.

Raychaudhuri S, Ripke S, Li M, Neale B, Fagerness J, Reynolds R . Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. Nat Genet. 2010; 42(7):553-5. PMC: 3138072. DOI: 10.1038/ng0710-553. View

19.

Hernandez-Fuentes M, Franklin C, Rebollo-Mesa I, Mollon J, Delaney F, Perucha E . Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study. Am J Transplant. 2018; 18(6):1370-1379. PMC: 6001640. DOI: 10.1111/ajt.14594. View

20.

Divers J, Ma L, Brown W, Palmer N, Choi Y, Israni A . Genome-wide association study for time to failure of kidney transplants from African American deceased donors. Clin Transplant. 2020; 34(6):e13827. PMC: 7694574. DOI: 10.1111/ctr.13827. View