Impact of SIRPα polymorphism on transplant outcomes in HLA‐identical living donor kidney transplantation

García-Sánchez, Cynthia; Casillas-Abundis, M Aurora; Pinelli, David F.; Tambur, Anat R.; Hod-Dvorai, Reut

doi:10.1111/ctr.14406

Cited by 7 publications

(4 citation statements)

References 52 publications

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“…SIRPα plays a crucial role as an inhibitory receptor for CD47 and is a key component of the “do-not-eat-me” signaling pathway, with potential implications in transplantation ( Garcia-Sanchez et al 2021 ). Similar to the HLA genes, the sequences encoding the extracellular domain of SIRPα exhibit the strongest signal.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection

Hayeck,

Li,

Mosbruger

et al. 2024

Genome Biology and Evolution

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Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection. LD-ABF demonstrated the most robust detection of selection in a variety of simulation scenarios, compared against a range of existing tests/tools (Tajima’s D, HKA, Dng, BetaScan, and BalLerMix). Furthermore, the impact of the quality of sequencing on detection of balancing selection was explored, as well, using: 1) SNP genotyping and exome data, 2) targeted high-resolution HLA genotyping (IHIW), and 3) whole-genome long-read sequencing data (Pangenome). In the analysis of SNP genotyping and exome data, we identified known targets and 38 new selection signatures in genes not previously linked to balancing selection. To further investigate the impact of sequencing quality on detection of balancing selection, a detailed investigation of the MHC was performed with high-resolution HLA typing data. Higher quality sequencing revealed the HLA-DQ genes consistently demonstrated strong selection signatures otherwise not observed from the sparser SNP array and exome data. The HLA-DQ selection signature was also replicated in the Pangenome samples using considerably less samples but, with high quality long-read sequence data. The improved statistical method, coupled with higher quality sequencing, leads to more consistent identification of selection and enhanced localization of variants under selection, particularly in complex regions.

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Section: Discussionmentioning

confidence: 99%

The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection

Hayeck,

Li,

Mosbruger

et al. 2024

Genome Biology and Evolution

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“…Tennessen et al also observed selection around SIRPA , though they did not identify nearly as strong of a signal–likely due to a combination of different sequencing platforms, sample sources, and methodology. SIRPα acts as an inhibitory receptor for CD47 and is a key component of the “do-not-eat-me” signaling pathway and may have implications in transplantations 47 . Similar to the HLA genes, the strongest signal appears in sequences coding for the extracellular domain of SIRPα 48 .…”

Section: Discussionmentioning

confidence: 99%

Improved detection of evolutionary selection highlights potential bias from different sequencing strategies in complex genomic-regions

et al. 2021

Preprint

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Balancing selection occurs when different evolutionary pressures impact the fitness of multiple alleles, resulting in increased allelic diversity in the population. A new statistical method was developed to test for selection, improving inference by using efficient Bayesian techniques to test for density and strength of linkage disequilibrium. Evolutionary simulation studies showed that the method consistently outperformed existing methods. Using this methodology, we tested for novel signals of balancing selection genome wide in 500 samples from phased trios. Several novel signals of selection appeared in CYP2A7, GPC6, and CNR2 across multiple ancestries. Additionally, tests in SIRPA demonstrate dramatically strong selection signal, significantly higher than previously observed. Well-known signals around olfactory genes and the MHC, containing HLA genes associated with the immune response, also demonstrated strong signatures of selection. So, utilizing data from the 17th IHIW, a follow up analysis was then performed by leveraging over seven thousand HLA typed samples by NGS; in contrast, the genome wide scan did not include a detailed characterization of the HLA genes. The strongest signals observed in the IHIW samples were in DQA1 and DQB1 in or around exon 2, the portion of the gene responsible for antigen presentation and most likely to be under environmental and evolutionary pressure. Our new statistical approach and analysis suggest novel evolutionary pressure in new regions and additionally highlight the importance of improved sequencing and characterization of variation across the extended MHC and other critical regions.

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“…In a small cohort of HLA-identical living donor kidney transplantation, they found a trend toward more graft failure, interstitial inflammation, and significant changes in peritubular capillaritis in the SIRPα-mismatched group. 29 Initial data from 375 patients suggest that donor-recipient SIRPα mismatches that modulate innate alloimmune responses are associated with increased acute rejection, premature interstitial fibrosis, tubular atrophy, and increased graft loss and are therefore important determinants of transplant success. 86 The negative effect on graft outcomes was found to be independent of HLA mismatch.…”

Section: Role Of Innate Alr In Clinical Transplantationmentioning

confidence: 99%

“… 24 Orthologs of both mouse PIR-A and CD47 have been identified in humans and they bind HLA molecules and human SIRPα, respectively, suggesting that innate recognition of allogeneic nonself could initiate alloimmune responses in humans as well. 28 , 29 Both classes of receptors are expressed on monocytes, and the engagement of these receptors by nonself MHC-I or SIRPα, respectively, causes differentiation of recipient monocytes into mature DC fully capable of activating the T cells responsible for rejection. It remains likely however that nonallogeneic factors such as PAMP or DAMP released during tissue damage or the intestinal microbiota potentiate monocyte maturation and APC activation at the time of transplantation via classical pattern recognition receptor.…”

Section: Introductionmentioning

confidence: 99%

Innate Allorecognition in Transplantation: Ancient Mechanisms With Modern Impact

Gui,

Al Moussawy,

Sanders

et al. 2023

Transplantation

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Through the effective targeting of the adaptive immune system, solid organ transplantation became a life-saving therapy for organ failure. However, beyond 1 y of transplantation, there is little improvement in transplant outcomes. The adaptive immune response requires the activation of the innate immune system. There are no modalities for the specific targeting of the innate immune system involvement in transplant rejection. However, the recent discovery of innate allorecognition and innate immune memory presents novel targets in transplantation that will increase our understanding of organ rejection and might aid in improving transplant outcomes. In this review, we look at the latest developments in the study of innate allorecognition and innate immune memory in transplantation.

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Impact of SIRPα polymorphism on transplant outcomes in HLA‐identical living donor kidney transplantation

Cited by 7 publications

References 52 publications

The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection

The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection

Improved detection of evolutionary selection highlights potential bias from different sequencing strategies in complex genomic-regions

Innate Allorecognition in Transplantation: Ancient Mechanisms With Modern Impact

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