Understanding regional genomic variation associated with risk and etiology of chronic aging diseases

Resumen

Resumen general y Fase I: Searching for explanations of common non-infectious diseases via single-nucleotide polymorphisms (SNPs) in the human genome that are common (i.e., present in ≥ 5% of chromosomes in a population of interest), or not rare (≥ 1%), is an active area of genetic research that is characterized by simple yet fertile open problems that are often easy to formulate, but a challenge to solve. Our umbrella project began with genotype-phenotype studies of a cohort from Medellín, Colombia, and was driven by our interest in improving our understanding of genetic causes of the related phenotypes of cardiovascular disease, type 2 diabetes and cardiometabolic syndrome. The most recent of 3 grants awarded to us by Colciencias (2013-2017) focused on chronic diseases that preferentially affect higher age groups, and allowed us to develop special ways of analyzing, interpreting and integrating genetic data from loci that are associated with disease traits. In the four years of the current project (2017-2020) we use these together with other methods to deepen our understanding of key ‘pleiotropic’ (multiple-effect) loci such as 9p21.3 and 12q24 and other trait-associated loci that have been well characterized at the molecular (e.g., gene regulation) level. We search for molecular-level causality within these loci, a problem that can often not be effectively tackled using only classical strategies such as distance-based fine mapping and SNP-by-SNP association-strength comparisons. We are also deepening our search into causes, physical and genetic, of heart and cardiovascular system ailments, including risk factors such as hypertension and symptoms of major health importance such as arrhythmias.Fase II: The second phase of the project for which we are requesting an extension has been made feasible by the results obtained and methodologies developed in the first phase, some of which have been published in our recent papers (one on locus 12q24 and introducing our basic methodology published in JACC, and one on locus 9p21.3 and making extensive and detailed use of our approach, published last month in IJC Hypertension). While cardiovascular and related diseases or syndromes (e.g., metabolic syndrome, diabetes type II) and hypertension remain the main focus or reference also in this second phase, due to our group’s specific expertise in these areas, we have widened the spectrum of diseases to which we apply our methods, to include genes involved in or associated with gallstone formation and disease (= cross-link to another project of our group), and to cancer/neoplastic or other diseases that we find are implicated in tradeoffs of balancing selection (antagonistic pleiotropy of common genetic variation associated with phenotypic traits affecting fitness).Although human host susceptibility to infecting pathogenic microbes is not strictly considered a chronic disease, its relation to genetic variation can be addressed using the same methodological approach, via haplotype classes, that we have developed in this project. A timely example is susceptibility to (a) establishing of a transmissible infection and (b) progression to severe respiratory symptoms requiring hospitalization, following exposure to the coronavirus responsible for Covid-19; a prime locus for (b) on chromosome 3 is adjacent to a prime susceptibility locus for cell entry of HIV, rendering it a particularly promising choice on which to focus. Our methods are inherently comparative in that they always characterize and contrast haplotype variation (e.g. via 1000 Genomes Project data) across all world populations, which can be related to documented epidemiological differences (geographical and/or ethnic).
Searching for explanations of common non-infectious diseases via single-nucleotide polymorphisms (SNPs) in the human genome that are common (i.e., present in ≥ 5% of chromosomes in a population of interest), or not rare (≥ 1%), is an active area of genetic research that is characterized by simple yet fertile open problems that are often easy to formulate, but a challenge to solve. Our umbrella project began with genotype-phenotype studies of a cohort from Medellín, Colombia, and was driven by our interest in improving our understanding of genetic causes of the related phenotypes of cardiovascular disease, type 2 diabetes and cardiometabolic syndrome. The most recent of 3 grants awarded to us by Colciencias (2013-2017) focused on chronic diseases that preferentially affect higher age groups, and allowed us to develop special ways of analyzing, interpreting and integrating genetic data from loci that are associated with disease traits. In the four years of the current project (2017-2020) we use these together with other methods to deepen our understanding of key ‘pleiotropic’ (multiple-effect) loci such as 9p21.3 and 12q24 and other trait-associated loci that have been well characterized at the molecular (e.g., gene regulation) level. We search for molecular-level causality within these loci, a problem that can often not be effectively tackled using only classical strategies such as distance-based fine mapping and SNP-by-SNP association-strength comparisons. We are also deepening our search into causes, physical and genetic, of heart and cardiovascular system ailments, including risk factors such as hypertension and symptoms of major health importance such as arrhythmias.

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2018-02-14 - 2026-12-31

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Understanding regional genomic variation associated with risk and etiology of chronic aging diseases Proyecto

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