Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

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.

Urological, vascular, and infectious implications of kidney transplant: a single-center experience / Complicaciones urológicas, vasculares e infecciosas del trasplante renal: experiencia en un solo centro

Introduction: Kidney transplant has improved in the last decades due to new technologies and surgical techniques. However, there are still multiple complications associated with this procedure, which can affect the function and viability of the kidney graft. Our aim was to describe the incidence of urological, vascular, and infectious complications in the 1st month after the procedure. Methods: A cross-sectional and retrospective study was carried out. Records of all patients who underwent kidney transplant from 2007 to 2017 were reviewed and data of demographic and surgical variables as well as information of vascular, urological, and infectious complications during the 1st post-operative month were registered and analyzed. Results: A total of 243 patients that required kidney transplant were assessed. The most common chronic kidney disease etiologies were: idiopathic (25.5%), glomerulopathies (24.7%), and hypertension (23.5%). Seventy patients (28.8%) presented a complication, of which 31 were urological, 27 were infectious, and 12 were vascular. In each category, the most frequent complications were the perirenal hematoma, the urinary tract infection, and renal artery stenosis, respectively. Conclusions: The prevalence of complications found in our center is similar to that reported in the literature and it is significant. It is important for medical personnel to be aware of this data to have a high level of suspicion and make an active search, as an early diagnosis and treatment of these pathologies are crucial to avoid graft loss

Introducción: El trasplante renal ha mejorado en las últimas décadas gracias a las nuevas tecnologías y técnicas quirúrgicas. Sin embargo, aún existen múltiples complicaciones asociadas a este procedimiento, que pueden afectar la función y viabilidad del injerto renal. Nuestro objetivo fue describir la incidencia de complicaciones urológicas, vasculares e infecciosas en el primer mes tras el procedimiento. Métodos: Se realizó un estudio retrospectivo de corte transversal. Se revisaron los expedientes de todos los pacientes que se sometieron a trasplante renal desde 2007 hasta 2017 y se registraron y analizaron datos de variables demográficas y quirúrgicas, así como información de complicaciones vasculares, urológicas e infecciosas durante el primer mes postoperatorio. Resultados: Se evaluaron un total de 243 pacientes que requirieron trasplante renal. Las etiologías de enfermedad renal crónica (ERC) más frecuentes fueron: idiopática (25,5%), glomerulopatías (24,7%) e hipertensión arterial (23,5%). 70 pacientes (28,8%) presentaron alguna complicación, de los cuales 31 fueron urológicos, 27 infecciosos y 12 vasculares. En cada categoría las complicaciones más frecuentes fueron el hematoma perirrenal, la infección del tracto urinario y la estenosis de la arteria renal respectivamente. Conclusiones: La prevalencia de complicaciones encontrada en nuestro centro es similar a la reportada en la literatura y es significativa. Es importante que el personal médico conozca estos datos para tener un alto nivel de sospecha y realizar una búsqueda activa, ya que el diagnóstico y tratamiento precoz de estas patologías es fundamental para evitar la pérdida del injerto.

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

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.