Polymorphisms in genes related to the complement system and antibody-mediated cardiac allograft rejection

Marrón-Liñares, Grecia M; Núñez, Lucı́a; Crespo-Leiro, María G.; Barge‐Caballero, Eduardo; Pombo, Jorge Reynolds; Paniagua‐Martin, María J.; Suárez-Fuentetaja, Natalia; Cid, Javier; Grille-Cancela, Zulaika; Muñiz, Javier; Tan, Carmela D.; Rodríguez, E. René; Vázquez‐Rodríguez, José Manuel; Hermida-Prieto, Manuel

doi:10.1016/j.healun.2017.07.006

Cited by 10 publications

(16 citation statements)

References 39 publications

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“…16,23,24,26 Thus, complement genes related to AMR seem to be important in recipients, and not in donors, as we have previously noted. 10 In contrast, all of the studies carried out in genes related to B-cell biology in transplantation noted a relationship with various outcomes: acute rejection; 28,30-32,34-36 graft associated with the absence of AMR. No SNP, however, in complement pathway genes, either in donor or in recipientdonor pairs, was associated with AMR.…”

Section: Recipient-donor Genotype Discrepancy and Amrmentioning

confidence: 99%

“…10 All samples were included in the next-generation sequencing (NGS) study using the TruSight One panel according to manufacturer instructions (Illumina, San Diego, CA, USA). The TruSight One is a commercial NGS panel for the targeted genomic enrichment of 4,813 genes including 51 genes related to the complement pathway and 61 genes related to the biology of B cells ( Table S1).…”

Section: Targeted Next-generation Sequencing Genetic Analysismentioning

confidence: 99%

“…10 Moreover, the minor allele frequency (MAF) of the SNP described was checked on two different databases: Single Nucleotide Polymorphism Database (dbSNP) and/or Exome Aggregation Consortium (ExAC).…”

Section: Databases and In Silico Toolsmentioning

confidence: 99%

“…7, 8 There have been many attempts to associate solid organ allograft outcomes with specific genetic variants, 9 but most studies have focused on recipient genotypes. Our group recently found that polymorphisms in recipients in complement 10 and in B-cell pathways (Núñez et al, unpublished H eart transplantation (HT) is a well-established lifesaving treatment for end stage cardiac failure. 1 Antibody-mediated rejection (AMR), however, represents one of the main problems for clinical management of HT because of its diagnostic complexity and poor evidence for supporting treatment.…”

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confidence: 99%

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Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation

Marrón-Liñares

Núñez

Crespo-Leiro

et al. 2018

Circ J

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Background: Heart transplantation (HT) is a well-established life saving treatment for end stage cardiac failure. Antibody-mediated rejection (AMR) represents one of the main problems after HT because of its diagnostic complexity and the poor evidence for supporting treatments. Complement cascade and B-cells play a key role in AMR and contribute to graft damage. This study explored the importance of variants in genes related to complement pathway and B-cell biology in HT and AMR in donors and in donorrecipient pairs. Methods and Results:Genetic variants in 112 genes (51 complement and 61 B-cell biology genes) were analyzed on next-generation sequencing in 28 donor-recipient pairs, 14 recipients with and 14 recipients without AMR. Statistical analysis was performed with SNPStats, R, and EPIDAT3.1. We identified one single nucleotide polymorphism (SNP) in donors in genes related to B-cell biology, interleukin-4 receptor subunit α (p.Ile75Val-IL4Rα), which correlated with the development of AMR. Moreover, in the analysis of recipient-donor genotype discrepancies, we identified another SNP, in this case in adenosine deaminase (ADA; p.Val178(p=)), which was related to B-cell biology, associated with the absence of AMR.Conclusions: Donor polymorphisms and recipient-donor discrepancies in genes related to the biology of B-cells, could have an important role in the development of AMR. In contrast, no variants in donor or in donor-recipient pairs in complement pathways seem to have an impact on AMR.

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Section: Recipient-donor Genotype Discrepancy and Amrmentioning

confidence: 99%

Section: Targeted Next-generation Sequencing Genetic Analysismentioning

confidence: 99%

Section: Databases and In Silico Toolsmentioning

confidence: 99%

mentioning

confidence: 99%

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Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation

Marrón-Liñares

Núñez

Crespo-Leiro

et al. 2018

Circ J

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“…Lowered concentrations in the blood may also indicate a problem with the properdin-producing cells as in neutropenia [ 9 ]. Few studies also found increased systemic properdin levels (Table 1 ), for example in IgA nephropathy and in patients on hemodialysis [ 15 , 18 , 22 , 97 , 98 ]. The observation that increased properdin levels were associated with cardiovascular events and reduced levels with chronic heart failure was somewhat contradicting and needs further examination [ 16 , 98 ].…”

Section: Clinical Significance Of Properdinmentioning

confidence: 99%

The role of properdin in complement-mediated renal diseases: a new player in complement-inhibiting therapy?

et al. 2018

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Properdin is known as the only positive regulator of the complement system. Properdin promotes the activity of this defense system by stabilizing its key enzymatic complexes: the complement alternative pathway (AP) convertases. Besides, some studies have indicated a role for properdin as an initiator of complement activity. Though the AP is a powerful activation route of the complement system, it is also involved in a wide variety of autoimmune and inflammatory diseases, many of which affect the kidneys. The role of properdin in regulating complement in health and disease has not received as much appraisal as the many negative AP regulators, such as factor H. Historically, properdin deficiency has been strongly associated with an increased risk for meningococcal disease. Yet only recently had studies begun to link properdin to other complement-related diseases, including renal diseases. In the light of the upcoming complement-inhibiting therapies, it is interesting whether properdin can be a therapeutic target to attenuate AP-mediated injury. A full understanding of the basic concepts of properdin biology is therefore needed. Here, we first provide an overview of the function of properdin in health and disease. Then, we explore its potential as a therapeutic target for the AP-associated renal diseases C3 glomerulopathy, atypical hemolytic uremic syndrome, and proteinuria-induced tubulointerstitial injury. Considering current knowledge, properdin-inhibiting therapy seems promising in certain cases. However, knowing the complexity of properdin's role in renal pathologies in vivo, further research is required to clarify the exact potential of properdin-targeted therapy in complement-mediated renal diseases.

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The role of properdin and Factor H in disease

Cortés

Desler

Mazzoli

et al. 2022

Advances in Immunology

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Polymorphisms in genes related to the complement system and antibody-mediated cardiac allograft rejection

Abstract: AMR is a complex phenotype affected by many recipient factors. Variants in p.Gly54Asp-MBL2 and p.Asn428(p=)-CFP genes, encoding mannose-binding lectin 2 and properdin, may influence the risk of AMR.

Cited by 10 publications

References 39 publications

Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation

Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody-Mediated Rejection After Heart Transplantation

The role of properdin in complement-mediated renal diseases: a new player in complement-inhibiting therapy?

The role of properdin and Factor H in disease

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