Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

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

Serum profiling identifies CCL8, CXCL13, and IL-1RA as markers of active disease in patients with systemic lupus erythematosus

IntroductionSystemic lupus erythematosus (SLE) is a clinically heterogeneous disease that presents a challenge for clinicians. To identify potential biomarkers for diagnosis and disease activity in SLE, we investigated a selected yet broad panel of cytokines and autoantibodies in patients with SLE, healthy controls (HC), and patients with other autoimmune diseases (AIDs).MethodsSerum samples from 422 SLE patients, 546 HC, and 1223 other AIDs were analysed within the frame of the European PRECISESADS project (NTC02890121). Cytokine levels were determined using Luminex panels, and autoantibodies using different immunoassays.ResultsOf the 83 cytokines analysed, 29 differed significantly between patients with SLE and HC. Specifically, CCL8, CXCL13, and IL-1RA levels were elevated in patients with active, but not inactive, SLE versus HC, as well as in patients with SLE versus other AIDs. The levels of these cytokines also correlated with SLE Disease Activity Index 2000 (SLEDAI-2K) scores, among five other cytokines. Overall, the occurrence of autoantibodies was similar across SLEDAI-2K organ domains, and the correlations between autoantibodies and activity in different organ domains were weak.DiscussionOur findings suggest that, upon validation, CCL8, CXCL13, and IL-1RA could serve as promising serum biomarkers of activity in SLE

O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases

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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

Eficacia del programa educativo “Por una sexualidad responsable” sobre los conocimientos de sexualidad en adolescentes del quinto año de secundaria de la Institución Educativa Adventista Puno, Puno, 2016

Objective: Was to determine the effectiveness of the educational program “For responsible sexuality” onthe knowledge of sexuality in adolescents of the fifth year of secondary school of the Adventist SchoolPuno- Puno, 2016. Methodology: The study was quantitative, quasi-experimental design, applying aPre and post test. The sample consisted of 51 adolescents aged 14 to 17, distributed in two groupsrandomly: experimental group and control group. A questionnaire on sexuality in adolescents was appliedto measure the level of knowledge. The results of the “control group”: in the pre-test a 48.1% low leveland 44.4% medium level, in the post test a result was shown similar to 48.1% at the low level and48.1% at the medium level. Resulted: In the “experimental group” before the application of the program50.0% presented a medium level and 33.3% a low level, only 16.7% a high level, in the post test theknowledge of adolescents was they increased to 83.3% with a high level and 16.7% a medium level, witha significant difference compared to the control group. Conclusion: that at a level of significance of (sig=, 000), the educational program was effective in improving knowledge about sexuality in adolescents.Objetivo: Fue determinar la eficacia del programa educativo “Por una sexualidad responsable” sobre losconocimientos de sexualidad en adolescentes del quinto año de secundaria de la I. E. Adventista Puno-Puno, 2016. Metodologia: El estudio fue de tipo cuantitativo, diseño cuasi experimental, aplicando unapre y post prueba. La muestra estuvo conformada por 51 adolescentes de 14 a 17 años, distribuidos endos grupos de manera aleatoria: grupo experimental y grupo control. Instrumento: Para medir el nivelde conocimiento se aplicó un cuestionario sobre sexualidad en adolescentes. Los resultados del “grupocontrol”: en el pre test un 48,1% nivel bajo y 44,4% nivel medio, en el post test se mostró un resultadosimilar de 48.1% en el nivel bajo y 48,1% en el nivel medio. Resultados: En el “grupo experimental”antes de la aplicación del programa el 50,0 % presentaron un nivel medio y 33,3% un nivel bajo, solo el16,7% un nivel alto, en el post test los conocimientos de los adolescentes se incrementaron a un 83,3% con un nivel alto y un 16,7% un nivel medio, habiendo diferencia significativa en comparación con elgrupo control. Conclusión: Que a un nivel de significancia de (sig= ,000), el programa educativo fueefectiva en la mejora de conocimientos sobre sexualidad en los adolescentes

The value of ABPM and subclinical target organ damage parameters in diagnosis of resistant hypertension

Introduction: We aimed to assess the effectiveness of ambulatory blood pressure monitoring (ABPM) and subclinical target organ damage parameters for diagnosis of resistant hypertension (RH). Methods: We assessed demographic and anthropometric variables, the incidence of cardiovascular events and subclinical target organ damage (n = 112). We also studied the relationship between these variables and the ABPM results. Results: Of the 112 patients referred from primary care with a diagnosis of RH, 69 (61.6%) were confirmed by ABPM. We found statistically significant differences (p < 0.001) between patients with RH and pseudo-resistant hypertension in the appearance of subclinical target organ damage. A percentage of 84 of the patients had microalbuminuria: 66.25 ± 30.7 mg/dl); 44.9% had stage 3 chronic kidney disease: the average glomerular filtration was 59 ml/min/1.73 m2; and 56.5% had left ventricular hypertrophy on echocardiography. Fundoscopy revealed that 64% of the patients had hypertensive retinopathy. Three variables were associated with an increased HR risk: microalbuminuria, hypertensive retinopathy and left ventricular hypertrophy (OR 5.7, 6.2 and 11.2, respectively). Conclusions: This study shows that the systematic testing for target organ damage, particularly in terms of albuminuria, is a simple and inexpensive tool, with a high predictive value for RH (85%), which could be useful for prioritizing patients who need ABPM. Resumen: Introducción: El presente estudio tiene como objetivo destacar la importancia de la monitorización ambulatoria de la presión arterial (MAPA) y de los parámetros de lesión subclínica de órgano diana en el diagnóstico de hipertensión refractaria (HR). Métodos: Se estudiaron pacientes con diagnóstico de HR (n = 112). Se analizaron variables demográficas, antropométricas, riesgo cardiovascular y lesión subclínica de órgano diana y se relacionaron con la confirmación de HR a través de la MAPA. Resultados: Del total de 112 pacientes con el diagnóstico de HR derivados desde atención primaria se confirmaron mediante MAPA el 61,6% de los casos (n = 69). Se observaron diferencias estadísticamente significativas (p < 0,001) en la aparición de lesión subclínica de órgano diana en los hipertensos refractarios respecto a los pseudorrefractarios. Un 84% de los pacientes con HR presentaban microalbuminuria: 66,25 ± 30,7 mg/dl). El 44,9% tienen una enfermedad renal crónica estadio 3 con filtrado glomerular medio de 59 ml/min/1,73 m2. El 56,5% presentaba hallazgos ecocardiográficos de hipertrofia de ventrículo izquierdo. El examen de fondo de ojo reveló que un 64% de los pacientes presentaban retinopatía hipertensiva. Las 3 variables que se asociaron a mayor riesgo de HR fueron la presencia de microalbuminuria, retinopatía hipertensiva e hipertrofia de ventrículo izquierdo por ecocardiograma (OR 5,7, 6,2 y 11,2, respectivamente). Conclusiones: Nuestro estudio demuestra que la búsqueda sistemática de daño de órgano diana, especialmente en lo referente a albuminuria, es una herramienta sencilla y barata, con un valor predictivo de HR alto (85%). Podría ser de utilidad en circunstancias en las que es necesario priorizar la realización de MAPA. Keywords: Ambulatory blood pressure monitoring, Resistant hypertension, Subclinical target organ damage, Palabras clave: Monitorización ambulatoria de la presión arterial, Hipertensión refractaria, Lesión subclínica de órgano dian

El valor de la MAPA y de los parámetros de lesión subclínica de órgano diana en el diagnóstico de hipertensión refractaria.

We aimed to assess the effectiveness of ambulatory blood pressure monitoring (ABPM) and subclinical target organ damage parameters for diagnosis of resistant hypertension (RH). We assessed demographic and anthropometric variables, the incidence of cardiovascular events and subclinical target organ damage (n=112). We also studied the relationship between these variables and the ABPM results. Of the 112 patients referred from primary care with a diagnosis of RH, 69 (61.6%) were confirmed by ABPM. We found statistically significant differences (P This study shows that the systematic testing for target organ damage, particularly in terms of albuminuria, is a simple and inexpensive tool, with a high predictive value for RH (85%), which could be useful for prioritising patients who need ABPM