Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Perfil de valores de estudiantes de carreras de salud del sur de Chile

Objetivo: Las instituciones de educación superior deben implementar en sus planes curriculares estrategias que posibiliten decisiones guiadas por principios y valores propios de cada profesión. El objetivo del estudio fue determinar el perfil de valores expresados por estudiantes de la salud en el sur de Chile.Materiales y métodos: Se trata de un estudio cuantitativo de corte transversal, descriptivo, con muestra intencionada de 242 (M=20,1 años) estudiantes de enfermería, psicología y kinesiología a quienes se aplicó el cuestionario Perfil de Valores Personales de Schwartz. Se utilizó el programa SPSS versión 20.0 para realizar un análisis de conglomerado jerárquico y verificar las dimensiones de valores asociadas entre sí, y se aplicó la prueba ANOVA de una vía con pruebas post hoc para verificar diferencias de medias en los puntajes de las subescalas de valores.Resultados: Se identificaron dos grandes conglomerados homogéneos: uno conformado por las dimensiones conformidad, seguridad, realización, tradición y benevolencia, y otro conformado por hedonismo y estímulo. En el análisis de medias, se observan diferencias estadísticamente significativas entre los grupos en las dimensiones universalismo, poder, autodirección, benevolencia, conformidad, tradición y realización (p<0,01). Las diferencias de medias más relevantes se encuentran entre las carreras de psicología y enfermería. En las dimensiones poder, conformidad y tradición, los estudiantes de kinesiología y enfermería presentan medias más altas que los de psicología (p<0,01).Conclusiones: Los resultados muestran un perfil valórico de los estudiantes de la salud. El siguiente paso debería ser la comparación del perfil resultante con el perfil valórico de egreso de cada disciplina, para favorecer el fortalecimiento de las dimensiones que cada carrera considera importantes para el desempeño profesional

Rare missense variant (R251G) on APOE counterbalances the Alzheimer’s disease risk associated with APOE-ε4

Background Despite decades of research, the mechanisms linking APOE to Alzheimer’s disease (AD) remain poorly understood. Finding additional risk variants at the APOE locus, beyond the common APOE-ε2 and APOE-ε4 alleles, may help elucidate how APOE is involved in the disease. Method Association with case-control status was tested in a sequenced discovery sample (Stage 1) and followed-up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (Stages 2+3) (Table 1). Stage 1 included 37,409 non-unique participants of European or Admixed-European ancestry, with 11,868 cases and 11,934 controls passing analysis inclusion criteria. In Stages 2+3, 475,473 participants were considered across 8 cohorts, of which 56,029 cases, 28,484 proxy-AD cases, and 328,372 healthy-controls passed inclusion criteria, and were of European ancestry. Result Two missense variants were associated with a two to three-fold decreased AD risk: R251G (odds ratio, 0.44; 95% confidence interval [CI], 0.33-0.59; P = 4.7×10-8) and V236E (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9×10-6) (Table 2, Figures 1, 2). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared to non-carriers (Table 3). Conclusion We identified a novel variant associated with AD, R251G, which mitigates the ε4 associated AD risk, and confirmed the protective effect of the V236E variant. The location of the variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here, suggest that protein chemistry and functional assays of these variants have the potential to identify novel pathways for drug development

Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences

Background Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases are responsible for considerable morbidity and mortality. With incidence rising with aging, these also represent a growing societal challenge. Pathophysiology involves accumulation of tau (neurofibrillary tangles) and Amyloid-β-rich (amyloid plaques) aggregates in AD, α-synuclein-rich aggregates (Lewy bodies) in PD and TDP-43 aggregates in ALS, although co-presence of these aggregates may occur. Consensus is also growing that tau may also play a key role in PD and ALS. Method Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with PD or Alzheimer’s AD disease versus controls across ancestry groups. Result A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. Conclusion An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

Predictors for anastomotic leak, postoperative complications, and mortality after right colectomy for cancer: Results from an international snapshot audit

Background: A right hemicolectomy is among the most commonly performed operations for colon cancer, but modern high-quality, multination data addressing the morbidity and mortality rates are lacking. Objective: This study reports the morbidity and mortality rates for right-sided colon cancer and identifies predictors for unfavorable short-term outcome after right hemicolectomy. Design: This was a snapshot observational prospective study. Setting: The study was conducted as a multicenter international study. Patients: The 2015 European Society of Coloproctology snapshot study was a prospective multicenter international series that included all patients undergoing elective or emergency right hemicolectomy or ileocecal resection over a 2-month period in early 2015. This is a subanalysis of the colon cancer cohort of patients. Main Outcome Measures: Predictors for anastomotic leak and 30-day postoperative morbidity and mortality were assessed using multivariable mixed-effect logistic regression models after variables selection with the Lasso method. Results: Of the 2515 included patients, an anastomosis was performed in 97.2% (n = 2444), handsewn in 38.5% (n = 940) and stapled in 61.5% (n = 1504) cases. The overall anastomotic leak rate was 7.4% (180/2444), 30-day morbidity was 38.0% (n = 956), and mortality was 2.6% (n = 66). Patients with anastomotic leak had a significantly increased mortality rate (10.6% vs 1.6% no-leak patients; p 65 0.001). At multivariable analysis the following variables were associated with anastomotic leak: longer duration of surgery (OR = 1.007 per min; p = 0.0037), open approach (OR = 1.9; p = 0.0037), and stapled anastomosis (OR = 1.5; p = 0.041). Limitations: This is an observational study, and therefore selection bias could be present. For this reason, a multivariable logistic regression model was performed, trying to correct possible confounding factors. Conclusions: Anastomotic leak after oncologic right hemicolectomy is a frequent complication, and it is associated with increased mortality. The key contributing surgical factors for anastomotic leak were anastomotic technique, surgical approach, and duration of surgery