[en] One of the main problems involved in heart transplantation (HT) is the humoral response now termed antibody-mediated rejection (AMR), where complement cascade and B-cells play a key role. Thus, in this doctoral thesis, we explore the importance of genes related to complement pathway and B-cell biology in heart transplant patients and their donors that can yield diagnostic and prognostic information about AMR. For this purpose, genetic variants in 112 genes (51 complement pathway and 61 B-cell biology genes) were analyzed by next generation sequencing in 46 HT patients, 23 with and 23 without AMR and 28 donors, 14 donors from patients with and 14 donors from patients without AMR. We have identified 7 polymorphisms (SNPs) between groups which correlates with the development of AMR: 5 SNPs in receptors: 2 SNPs in complement genes (p.Gly54Asp- MBL2 and p.Asn428(p=)-CFP) and 3 SNPs in ITGA4 gene, related with B-cell biology [p.Thr615(p=), p.Gln878Arg y p.His961(p=)]. We have identified one SNP in donors in genes related with B-cell biology, p.Ile75Val-IL4Rα, which correlates with the development of AMR. Moreover, in the analysis of discrepancies between recipientdonor genotypes, we have identified another SNP, in this case in ADA gene (p.Val178(p=)), which is related with B-cell biology, associated with AMR. In addition, to examine the role of the variants p.Gly54Asp-MBL2, p.Asn428 (p =)-CFP and for the AGT-ITGA4 haplotype, expression studies were carried out, in patients with presence and absence of these variants, that corroborated their possible role in the development of the AMR. The most relevant conclusion of this study is that polymorphisms in HT receptors in MBL2 and CFP genes of the complement pathway and polymorphisms in ITGA4, IL4Rα, and ADA genes belonging to the B cells biology in HT receptors and in donors could have an important role in AMR.

[gl] Unha das principais complicacións tras o transplante cardíaco é a aparición do rexeitamento mediado por anticorpos (RMA), onde a cascada do complemento e as células B xogan un papel fundamental. Nesta tese de doutoramento nos plantexamos o estudo dos xenes implicados na bioloxía das células B e na activación da cascada do complemento, en pacientes transplantados e nos seus doantes que aportan información diagnóstica e prognóstica sobre o RMA. Para iso, analizáronse as variantes xenéticas detectadas en 112 xenes, 51 xenes relacionados coa vía do complemento e 61 xenes implicados na bioloxía das células B en 46 receptores con TC, 23 con RMA e 23 sen RMA e en 28 doantes, 14 doantes dos pacientes con RMA e 14 doantes dos pacientes sen RMA. Identificáronse 7 polimorfismos (SNP) con diferenzas significativas entre ambos grupos: 5 SNPs presentes en receptores: 2 SNPs en xenes da vía do complemento (p.Gly54Asp-MBL2 y p.Asn428(p=)-CFP) e 3 SNPs no xen ITGA4 implicado na bioloxía das células B [p.Thr615(p=), p.Gln878Arg y p.His961(p=)]. Un SNP no xen IL4Rα (p.Ile75Val), relacionado coa bioloxía das células B, nos doantes e un SNP no xen ADA (p.Val178(p=)), que participa na regulación das células B, nas parexas doantereceptor con TC. Ademais, para examinar o papel das variantes p.Gly54Asp-MBL2, p.Asn428(p=)-CFP e para o haplotipo AGT-ITGA4, leváronse a cabo estudos de expresión en pacientes, con presenza e ausencia de ditas variantes, que corroboraron o seu posible papel no desenvolvemento do RMA. A conclusión máis relevante deste estudo é que os polimorfismos presentes nos xenes MBL2 e CFP da vía do complemento, en receptores con TC, e nos xenes ITGA4, IL4Rα e ADA, nas células B, en receptores con TC e en doantes, xogan un importante papel no RMA.