Abstract
IntroductionOne of the main problems involved in heart transplantation (HT) is antibody-mediated rejection (AMR). Many aspects of AMR are still unresolved, including its etiology, diagnosis and treatment. In this project, we hypothesize that variants in genes involved in B-cell biology in HT patients can yield diagnostic and prognostic information about AMR.MethodsGenetic variants in 61 genes related to B-cell biology were analyzed by next generation sequencing in 46 HT patients, 23 with and 23 without AMR.ResultsWe identified 3 single nucleotide polymorphisms in ITGA4 gene (c.1845G>A, c.2633A>G, and c.2883C>T) that conformed the haplotype AGT-ITGA4. This haplotype is associated with the development of AMR. Moreover, AMR patients with the haplotype AGT-ITGA4 present lower levels of integrin α-4 in serum samples compared to the reference GAC haplotype in control patients.ConclusionWe can conclude that polymorphisms in genes related to the biology of B-cells could have an important role in the development of AMR. In fact, the AGT haplotype in ITGA4 gene could potentially increase the risk of AMR.
Highlights
One of the main problems involved in heart transplantation (HT) is antibody-mediated rejection (AMR)
We identified 3 single nucleotide polymorphisms in ITGA4 gene (c.1845G>A, c.2633A>G, and c.2883C>T) that conformed the haplotype AGT-ITGA4
The main results of this study are: 1.) AGT haplotype is associated with the development of AMR and 2.) integrin α-4 serum levels in patients carried AGT haplotype are lower that patients carried the reference GAC haplotype
Summary
Genetic variants in 61 genes related to B-cell biology were analyzed by generation sequencing in 46 HT patients, 23 with and 23 without AMR. This is a retrospective case-control study to evaluate a set of 61 genes related to the biology of B-cells (S1 Fig, S1 Table) and its association with AMR in HT patients from the Advanced Heart Failure and Transplant Unit of the Complejo Hospitalario Universitario de A Coruña (CHUAC). PAMR1(H+)-histopathologic AMR alone: histopathologic findings present and immunopathologic findings negative. PAMR1(I+)-immunopathologic AMR alone: histopathologic findings negative and immunopathologic findings positive; that is, CD68+ and/or C4d+ for IHC and C4d+ with or without C3d+ for IF. PAMR2-pathologic AMR: histopathologic and immunopathologic findings are both present. In AMR patients, the inclusion criteria was having at least one positive endomyocardial biopsy (pAMR1 or higher)
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