Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia.

BACKGROUND: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. OBJECTIVE: We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG. METHODS: We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions. RESULTS: We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis. CONCLUSIONS: Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.

MAPK and PI3K activities are required for leptin stimulation of protein synthesis in human trophoblastic cells.

Leptin, the LEP gene product, is produced in placenta where it has been found to be an important autocrine signal for trophoblastic growth during pregnancy. Thus, we have recently described the antiapoptotic and trophic effect of leptin on choriocarcinoma cell line JEG-3, stimulating DNA and protein synthesis. We have also demonstrated the presence of leptin receptor and leptin signaling in normal human trophoblastic cells, activating JAK-STAT, PI3K and MAPK pathways. In the present work we have employed dominant negative forms of MAPK and PKB constructs to find out the signaling pathways that specifically mediates the effect of leptin on protein synthesis. As previously shown, leptin stimulates protein synthesis as assessed by (3)H-leucine incorporation. However, both dominant negative forms of MAPK and PKB inhibited protein synthesis in JEG-3 choriocarcinoma cells. The inhibition of PKB and MAPK activity by transfection with the dominant negative kinases prevented the leptin stimulation of p70 S6K, which is known to be an important kinase in the regulation of protein synthesis. Moreover, leptin stimulation of phosphorylation of EIF4EBP1 and EIF4E, which allows the initiation of translation was also prevented by MAPK and PI3K dominant negative constructs. Therefore, these results demonstrate that both PI3K and MAPK are necessary to observe the effect of leptin signaling that mediates protein synthesis in choriocarcinoma cells JEG-3.

Cumplimiento de objetivos terapéuticos en pacientes con revascularización miocárdica en el Área Virgen Macarena de Sevilla / Achievement of therapeutic goals in patients with myocardial revascularization in Virgen Macarena’s Hospital

Introducción. La revascularización miocárdica es una intervención terapéutica perfectamente establecida en pacientes con enfermedad coronaria. El objetivo del presente estudio es el de comprobar el cumplimiento terapéutico de los objetivos marcados por el Adult Treatment Panel (ATP) III para una población de muy alto riesgo cardiovascular y la evolución de los principales factores de riesgo cardiovascular. Material y métodos. Se han estudiado un total de 131 pacientes intervenidos de bypass aortocoronario. Para la evaluación de su riesgo y posterior tratamiento, fueron atendidos a los 3, 6 y 12 meses tras la intervención. Independientemente de otros datos necesarios para la historia clínica, a todos se les determinó los valores de presión arterial, perímetro de cintura, peso, talla e índice de masa corporal, hábito tabáquico y hemograma, un perfil bioquímico y un perfil de riesgo cardiovascular que incluye, además de los habituales, una ultracentrifugación para la separación de las lipoproteínas, los valores de apolipoproteína (apo) A-I y B-100 y diversos marcadores de riesgo e inflamación como la lipoproteína(a) (Lp[a]), proteína C reactiva ultrasensible (PCR), el fibrinógeno y la homocisteína. Resultados. Los valores de colesterol unido a lipoproteínas de baja densidad (cLDL) descendieron desde 142 a 108 mg/dl y los de apo B desde 101 a 79 mg/dl. El 44% de los pacientes cumplió los objetivos marcados por el ATP III, es decir, cLDL 102 cm, presente en el 50% de los pacientes, descendió al 19,64%, y los fumadores, que abarcaban el 58% de los pacientes, abandonaron en su totalidad el hábito tabáquico. Conclusiones. Tras el tratamiento con estatinas y/o estatinas-ezetimiba y modificación de los hábitos de vida, los pacientes experimentan una reducción significativa de los principales factores de riesgo a excepción de la homocisteína y de la Lp(a); el 44% de los pacientes estudiados cumple los objetivos marcados por el ATP III. Por otro lado, el tratamiento combinado estatina-ezetimiba parece producir mayores beneficios que el tratamiento con estatinas en monoterapia (AU)

Introduction. Myocardial revascularization is a well established therapeutic intervention in coronary disease. The aim of the present study was to asses the achievement of the therapeutic goals recommended by the Adult Treatment Panel (ATP) III in patients with high risk for cardiovascular disease. Material and methods. We have studied 131 patients with a previous aorto-coronary bypass. In order to evaluate their cardiovascular risk and their pharmacological treatment, we have followed the patients 3, 6 and 12 months after the intervention. In addition to the medical history, we measured blood pressure, waist circumference, weight, height, body mass index (BMI), smokers, non smokers, haematology test, biochemical and cardiovascular profile. To complete the cardiovascular study we determined cholesterol fractions. The serum samples were ultracentrifuged to separate lipoproteins, and measure the levels of apolipoproteins (Apo) A1 and B 100 and several markers of cardiovascular risk and inflammation such as lipoprotein (Lp) (a), ultra sensitive C reactive protein (CPR), fibrinogen and homocysteine. Results. The levels of lowdensity lipoprotein (LDL) decreased from 142 mg/dl to 108 mg/dl and Apo B levels from 101 mg/dl to 79 mg/dl. The therapeutic goals recommended by ATP III were achieved by 44% of patients, that is a cLDL < 100 mg/dL. We observed changes in other risk factors in our population study. The number of overweight patients decreased from 42% to 12%, and obese patients from 27% to 10%. Those patients with a waist circumference greater than 102 cm decreased from 50% to 19.64% and 58% of the smokers gave it up. Conclusions. The patients showed a significant reduction in the major risk factors with no changes in the homocysteine and Lp (a) levels. After treatment with statins and/or statins- ezetimibe) 44% of the patients achieved the therapeutic goals suggested by ATP III. The combined treatment (statins + ezetimibe) seems to be more effective than therapy with statins only (AU)