Tesis Doctorales
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Browsing Tesis Doctorales by Author "Calderón Giadrosic, Juan Francisco"
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Item Genetic modifiers associated with the variability of the aortic phenotype in patients with inheritable connective tissue disorders(ICTDs)(Universidad del Desarrollo. Facultad de Medicina, 2022-05-27) Jiménez Bejarano, Yanireth José; Calderón Giadrosic, Juan FranciscoInheritable Connective Tissue Disorders (ICTDs) are rare genetic diseases that involve variants in genes that encode for proteins of the extracellular matrix (ECM). ICTDs affect patients from birth and their symptoms are present in the cardiovascular system, musculoskeletal system, the skin, the eye and the respiratory system. This family of diseases includes Marfan Syndrome (MFS), Loeys-Dietz Syndrome types I, II, III and IV (LDS), Ehlers- Danlos Syndrome type IV (vEDS), among others, and are caused by variants in genes that code for different effectors or regulators of the Transforming Growth Factor beta (TGFβ) signaling pathway, including genes that encode for ECM components that play active roles in the signaling activity of this pathway. The cardinal feature of these diseases is the enlargement and rupture of big vessels and, most prominently, the aorta. Aneurysm and dissection of the aorta is the main cause of mortality in these patients but the clinical course of MFS and other ICTDs differs considerably in terms of age of onset and severity, even among individuals who share the same causative variant. This led us to hypothesize the existence of genetic variants elsewhere in the genome that influence the severity of the cardiovascular phenotype in MFS. We recruited familial and sporadic MFS patients that were subsequently classified as having severe (n=8) or mild aortic phenotype (n=14) according to the age of presentation of the first cardiovascular manifestation and/or catastrophe related to the aorta. We used Exome Sequencing (ES) to identify genetic variants that may be associated with the severity of this clinical manifestation, and we performed linkage analysis using the software VAAST. We identified 5 genes associated with severe aortic phenotype and 3 genes that could be protective of this phenotype in MFS. These genes regulate components of the ECM, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM and/or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management strategies and, potentially, new therapies for these patients.Publication Reconstruction of the evolution of the Chilean-Cordobes clone of methicilin resistant: Staphylococcus aureus in Latin America(Universidad del Desarrollo. Facultad de Medicina, 2023) Martínez Solís, José Rodrigo Waldemar; Munita, José; Calderón Giadrosic, Juan FranciscoThe global dissemination of methicillin-resistant Staphylococcus aureus (MRSA) is associated with the emergence and establishment of clones in specific geographic areas. The MRSA Chilean-Cordobes clone (ChC) predominated widely throughout several countries of Latin America, but during the mid-2000s the USA300-SAE clone quickly replaced the ChC in Colombia and Ecuador. Most notably, this replacement was not observed in Peru or Chile, where the ChC remains as the most frequent clone. Here, we aimed to perform a phylogenomic reconstruction of the evolution of the ChC in Latin America and to estimate the effect on the fitness of genetic features that are particular to the ChC clone from Chile. To achieve this aim, we sequenced 925 genomes of MRSA strains from Latin America. First, we performed whole genome sequencing and confirmed that the ChC clone remains the most frequent clone in our country. However, this lineage has been gradually replaced, in a nontypical MRSA clonal replacement event, by new emerging clones (ST105-SCCmecII and ST72-SCCmecVI). Then, we explore the impact of heavy metal resistance genes in the evolution of the ChC clone and provide evidence to suggest a possible link between the release of high quantities of heavy metals in the aftermath of an environmental disaster and the divergent evolution of the ChC in Latin America. Finally, we found evidence that the Sau1 restriction modification system plays a key role in the genomic evolution of the Chilean-Cordobes clone in Latin America by increasing the acquisition of foreign DNA. Overall, these results have the potential to greatly enhance our understanding of MRSA dissemination and contribute to improved approaches for combating this pathogen in Chile and Latin America.