ABSTRACT
Introducción. El cáncer colorrectal es una carga para la salud pública en Colombia y el mundo. Estudios de asociación genética han identificado regiones cromosómicas asociadas a esta enfermedad, mostrando riesgo variable entre poblaciones, debido a la historia demográfica y la ancestría genética. Objetivo. Estudiar el riesgo que aportan 20 marcadores al cáncer colorrectal en Colombia, empleando 955 casos y 972 controles del consorcio CHIBCHA, analizando conjuntamente el efecto de la ancestría genética global y local. Metodología. Las muestras se genotipificaron usando microarreglos Axyom Affymetrix LAT y CUSTOME, para obtener los genotipos genómicos globales, incluyendo 20 SNPs de riesgo. Los análisis estadísticos se realizaron en PLINK (asociaciones), ADMIXTURE (ancestría global), Elai (ancestría local) y R (modelos logísticos). Resultados. Once regiones cromosómicas resultaron asociadas presentando ORs entre 1.14 y 1.41 (p<0.05): 18q21.1, 19q13.11, 10p14, 14q.2.2, 20p12.3, 8q23.3, 6p21.2, 15q13.3 y 8q24.21. Una mayor ancestría europea se asoció con el riesgo a nivel global (OR=3.016, IC 95%:1.162-7.894, p=0.00325), y a nivel cromosómico local se detectaron las regiones 6q23.2 (ORajustado=1.378, IC95%: 1.202-1.580, Pajustado=4.2e-6) y 4p13 (ORajustado=1.301, IC95%:1.137-1.489; Pajustado=0.00013). Conclusiones. La ancestría podría considerarse un factor en la explicación de la susceptibilidad en Colombia, indicando que la mezcla genética de origen amerindio y europeo, influye en la estructura poblacional y explicaría las diferencias en la incidencia del CCR entre poblaciones latinas y europeas.
Introduction: Colorectal cancer is a public health burden in the world and Colombia. Recent genome wide association studies have identified chromosomal regions associated with the disease, depicting variable risk between populations, owing to the demographic history and genetic ancestry. Objective: We aimed to study the colorectal cancer risk in Colombia provided for 20 genetic markers, by using 955 cases and 972 controls from the CHIBCHA consortium, in the context of global and local genetic ancestry. Methodology: The samples were genotyped using Axyom Affymetrix LAT and CUSTOME array in order to obtain the global genome genotypes including 20 risk SNPs. Statistical analysis was performed in PLINK (associations), ADMIXTURE (global ancestry), Elai (local ancestry) and R language (logistic models). Results: Eleven chromosomal regions were associated with ORs ranging between 1.14-1.41 (p<0.05): 18q21.1, 19q13.11, 10p14, 14q.2.2, 20p12.3, 8q23.3, 6p21.2, 15q13.3 y 8q24.21. On average, a higher global European ancestry was associated with colorectal cancer risk (OR=3.016, IC 95%:1.162-7.894, p=0.00325). At the local chromosomal level two regions presented a significant increment of European ancestry 6q23.2 (OR adjusted=1.378, CI95%: 1.202-1.580, p adjusted =4.2e-6) and 4p13 (OR adjusted =1.301, CI95%:1.137-1.489; p adjusted =0.00013). Conclusions: Genetic ancestry can be considered as a relevant factor for the colorectal cancer susceptibility in Colombia. Both Native American and European ancestry are accounting for the most part of population structure in the sample we studied, which could explain the differences for the colorectal cancer incidence between Latin American and European populations.
Subject(s)
Humans , Genetic Association Studies , Colorectal Neoplasms , Colombia , Genetic Predisposition to DiseaseABSTRACT
Las reacciones anapleróticas son un mecanismo metabólico esencial para la continuidad postnatal del desarrollo cerebral, contribuyendo en procesos que requieren sustratos sintetizados a partir de intermediarios del ciclo de Krebs; sin embargo, se desconoce su papel en el neonato durante la prelactancia. Objetivo. Estimar la capacidad anaplerótica de neuronas y astrocitos crecidos in vitro. Materiales y métodos. Se midió el efecto del 3-nitropropionato (3-NPA)(2 mM), un inhibidor de Succinato Deshidrogenasa (SDH) sobre el metabolismo oxidativo y lipogénico de 14C derivados de acetato y lactato en concentraciones perinatales. Resultados. A pesar de la presencia del 3-NPA, se mantuvieron las velocidades de oxidación del lactato en neuronas y astrocitos en un 40 y 73% respectivamente y la lipogénesis en un 53 y 52% respectivamente. Con el acetato, la oxidación en neuronas y astrocitos se mantuvo en un 15 y 63% respectivamente, en tanto que la lipogénesis se mantuvo en astrocitos y aumentó en neuronas en un 174% (p<0,05). Todo esto comparado con sus respectivos controles sin inhibidor...
3-Nitropropionate effect on the lactate and acetate metabolism of neurons and astrocytes grown in vitro with perinatal concentrations.Anaplerotic reactions are an essential metabolic mechanism for the postnatal continuity of the brain development, contributing in processes that require substrates synthesized from Krebs cycle intermediates; however, their role during the presuckling period in theneonate is unknown. Objective. To estimate the anaplerotic capacity of neurons and astrocytes grown in vitro under perinatal conditions.Materials and methods. The effect of 3-nitropropionate (3-NPA)(2 mM) an inhibitor of the succinate dehydrogenase (SDH) on the oxidative and lipogenic metabolism of 14C-derived from acetate and lactate in perinatal concentrations. The results were compared with itsrespective controls without inhibitor. Results. In spite of the presence of 3-NPA, respiratory activity with lactate was 40% in neurons and73% in astrocytes, the lipogenesis was 53% in neurons and 52% in astrocytes. With acetate, the oxidation in neurons was 15% and 63% in astrocytes, lipogenesis was maintained in astrocytes but in neurons it increased up to 174% (p<0.05). Conclusions. These results demonstrate that in spite the oxalacetate depletion generated by 3-NPA, neurons as well as astrocytes are able to maintain the energeticmetabolism and the lipid synthesis using lactate or acetate thanks to the anaplerotic activity in the presuckling period. Additionally, astrocytes showed a capacity of buffering the effects of 3-NPA on the oxidation process greater than the neuron capacity. Neurons and astrocytes revealed a better capacity of directing acetate for lipid synthesis, activating the cytosolic acetyl-CoA synthetase pathway...
Efeito do 3-nitropropionato sobre o metabolismo do lactato e do acetato em neuronios e astrocitos crescidos in vitro em concentrações perinatales. As reações anapleróticas são um mecanismo metabólico essencial para a continuidade pos-natal do desenvolvimento cerebral,contribuindo nos processos que precisam substratos sintetizados a partir de intermediários do ciclo de Krebs. Embora, seu papel é desconhecido no neonato durante a prelactancia. Objetivo. Estimar a capacidade anaplerótica de neuronios e astrocitos crescidos in vitro.Materiais e métodos. Quantificou-se o efeito do 3-nitropropionato (3-NPA)(2 mM), um inibidor do Succinato Deshidrogenasa (SDH), sobre o metabolismo oxidativo e lipogénico de 14C derivados de acetato e lactato em concentrações perinatais. Resultados. A pesar da presença do 3-NPA, mantiveram-se as velocidades de oxidação do lactato em neuronas e astrocitos num 40 e 73% respectivamente e a lipogenesis em 53 e 52% respectivamente. Com o acetato, a oxidação em neuronas e astrocitos mantive-se num 15 a 63% respectivamente, no em tanto, a lipogénesis mantive-se em astrocitos e aumento em neuronas num 174% (p<0,05). Tudo o anterior comparado com seus respectivos controles sem inibidor. Conclusões. Estes resultados demonstram que a pesar da depleção do oxalacetato gerada pelo 3-NPA,as neuronas como os astrocitos são capazes de manter na prelactancia o metabolismo energético e a síntese de lípidos empregando lactato ou acetato devido à atividade anaplerótica. Adicionalmente, os astrocitos demonstraram ter maior capacidade de amortecer os efeitos do 3-NPA sobre a oxidação que as neuronas. As neuronas e os astrocitos apresentaram uma maior capacidade de dirigir o acetato para a síntese de lipídeos, ativando a via Acetil-CoA sintetasa citosólica...