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

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

Vasopressin serum levels and disorders of sodium and water balance in patients with severe brain injury Níveis séricos de vasopressina e distúrbios de sódio e água em pacientes com lesão cerebral grave

BACKGROUND: Disorders of water and sodium balance are frequently seen in patients with severe brain injury (SBI), and may worsen their prognosis. PURPOSE: To evaluate vasopressin (AVP) serum levels and sodium and water balance disorders during the first week post-injury in patients with SBI. METHOD: Thirty-six adult patients with SBI (admission Glasgow Coma Scale score < 8) and an estimated time of injury < 72 hours were prospectively studied. Clinical and laboratory data were recorded and AVP was measured in venous blood samples collected on the 1st, 2nd, 3rd and 5th days following inclusion. RESULTS: AVP serum levels remained within the normal range in SBI patients (either traumatic or non-traumatic), although tended to be greater in non-survivor than in survivor patients (p=0.025 at 3rd day). In-hospital mortality was 43% (15/36), and serum sodium and plasma osmolality variabilities were greater in non-survivor than in survivor patients during the observation period (p<0.001). CONCLUSION: AVP serum levels remained within the normal range values in these SBI patients, but those who died have shown higher incidence of abnormal sodium and water balance during the first week post-injury.<br>ANTECEDENTES: Desordens do balanço de água e sódio são frequentemente vistas em pacientes com lesão cerebral grave (LCG), podendo agravar o prognóstico. OBJETIVO: Avaliar os níveis séricos de vasopressina (AVP) e a incidência de distúrbios da água e sódio na primeira semana pós-lesão em pacientes com LCG. MÉTODO: Trinta e seis pacientes adultos com LCG (pontuação inicial na escala de coma de Glasgow < 8) e tempo estimado de lesão < 72h foram estudados prospectivamente. Dados laboratoriais e clínicos foram registrados e os níveis séricos de AVP foram mensurados no 1º, 2º, 3º e 5º dias pós-inclusão. RESULTADOS: A AVP manteve-se dentro da faixa de normalidade nestes pacientes, mas mostrando-se proporcionalmente mais elevada nos pacientes que não sobreviveram (p=0,025 no 3º dia). A mortalidade intra-hospitalar foi 43% (15/36) e as variações do sódio e osmolalidade plasmáticos foram maiores nos pacientes que não sobreviveram durante o período de observação (p<0,001). CONCLUSÃO: Os níveis séricos de AVP mantiveram-se dentro da faixa de normalidade nestes pacientes com LCG, mas aqueles não sobreviventes mostraram maior incidência de anormalidades do balanço de água e sódio durante a primeira semana de evolução

The expanding role of primary care in cancer control

The nature of cancer control is changing, with an increasing emphasis, fuelled by public and political demand, on prevention, early diagnosis, and patient experience during and after treatment. At the same time, primary care is increasingly promoted, by governments and health funders worldwide, as the preferred setting for most health care for reasons of increasing need, to stabilise health-care costs, and to accommodate patient preference for care close to home. It is timely, then, to consider how this expanding role for primary care can work for cancer control, which has long been dominated by highly technical interventions centred on treatment, and in which the contribution of primary care has been largely perceived as marginal. In this Commission, expert opinion from primary care and public health professionals with academic and clinical cancer expertise—from epidemiologists, psychologists, policy makers, and cancer specialists—has contributed to a detailed consideration of the evidence for cancer control provided in primary care and community care settings. Ranging from primary prevention to end-of-life care, the scope for new models of care is explored, and the actions needed to effect change are outlined. The strengths of primary care—its continuous, coordinated, and comprehensive care for individuals and families—are particularly evident in prevention and diagnosis, in shared follow-up and survivorship care, and in end-of-life care. A strong theme of integration of care runs throughout, and its elements (clinical, vertical, and functional) and the tools needed for integrated working are described in detail. All of this change, as it evolves, will need to be underpinned by new research and by continuing and shared multiprofessional development