RESUMEN
INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.
Asunto(s)
Enfermedad de Alzheimer , Clusterina , Humanos , Clusterina/genética , Colombia , Enfermedad de Alzheimer/diagnóstico , Mutación/genética , Amiloide , Presenilina-1/genética , Edad de InicioRESUMEN
BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.
Asunto(s)
Enfermedad de Alzheimer , Degeneración Lobar Frontotemporal , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/genética , Colombia , Efecto Fundador , Degeneración Lobar Frontotemporal/genética , Humanos , Mutación , Enfermedades Neurodegenerativas/genéticaRESUMEN
La obesidad se considera un importante factor de riesgo para varias enfermedades tales como hipertensi'on arterial, diabetes mellitus, enfermedad coronaria, ateroesclerosis, hipertrigliceridemia e hipercolesterolemia. Se estima que en el mundo la prevalencia de obesidad en la población adulta es de 20 a 50 por ciento, según el criterio y la definición empleados. La Asociación colombiana de obesidad y metabolismo (AS-COM), ha desarrollado un trabajo en equipo a lo largo de 1995, encaminado a elaborar recomendaciones generales que sirven como base para un consenso nacional sobre el enfoque y manejo del paciente obeso yno de la obesidad. El principal objetivo del presente trabajo es llevar al médico general y al paciente obeso, un concepto científico sobre la definición, patogenesis, etiología, clasificación y diagnostico de la obesidad, además de proporcionarle una guía práctica sobre su correcto manejo médico.
