The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.We thank members of the Cambridge BioResource Scientific Advisory Board and Management Committee for their support of our study and the National Institute for Health Research Cambridge Biomedical Research Centre for funding. K.D. is funded as a HSST trainee by NHS Health Education England. M.F. is funded from the BLUEPRINT Grant Code HEALTH-F5-2011-282510 and the BHF Cambridge Centre of Excellence [RE/13/6/30180]. J.R.S. is funded by a MRC CASE Industrial studentship, co-funded by Pfizer. J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and National Institute for Health Research (NIHR) Senior Investigator. S.M., S.T, M.H, K.M. and L.D. are supported by the NIHR BioResource-Rare Diseases, which is funded by NIHR. Research in the Ouwehand laboratory is supported by program grants from the NIHR to W.H.O., the European Commission (HEALTH-F2-2012-279233), the British Heart Foundation (BHF) to W.J.A. and D.R. under numbers RP-PG-0310-1002 and RG/09/12/28096 and Bristol Myers-Squibb; the laboratory also receives funding from NHSBT. W.H.O is a NIHR Senior Investigator. The INTERVAL academic coordinating centre receives core support from the UK Medical Research Council (G0800270), the BHF (SP/09/002), the NIHR and Cambridge Biomedical Research Centre, as well as grants from the European Research Council (268834), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), Merck and Pfizer. DJR and DA were supported by the NIHR Programme ‘Erythropoiesis in Health and Disease’ (Ref. NIHR-RP-PG-0310-1004). N.S. is supported by the Wellcome Trust (Grant Codes WT098051 and WT091310), the EU FP7 (EPIGENESYS Grant Code 257082 and BLUEPRINT Grant Code HEALTH-F5-2011-282510). The INTERVAL study is funded by NHSBT and has been supported by the NIHR-BTRU in Donor Health and Genomics at the University of Cambridge in partnership with NHSBT. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health of England or NHSBT. D.G. is supported by a “la Caixa”-Severo Ochoa pre-doctoral fellowship

The genetic determinants of recurrent somatic mutations in 43,693 blood genomes

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Infections in nursing homes (epidemiology, control and preventability)

Les infections représentent un problème majeur de santé publique dans les institutions gériatriques. En France, dans les Établissements d Hébergement pour Personnes Âgées Dépendantes (EHPAD), très peu d études ont exploré le risque infectieux bien que 443 765 personnes âgées soient institutionnalisées dans 6 460 maisons de retraite et EHPAD (d après extraction de la base ministérielle FINESS des établissements médicaux et médico-sociaux, au 1er janvier 2006). En 2005, missionné par le Ministère délégué aux personnes âgées, une unité de recherche tournée vers une meilleure compréhension et une stratégie offensive vis-à-vis des risques infectieux en gériatrie, l Observatoire du Risque Infectieux en Gériatrie (ORIG), a réalisé une enquête pilote de prévalence dans le Val de Marne (94): le taux de prévalence des infections est estimée à 14.5% [Intervalle de confiance à 95% (IC 95%): 13.0 16.0]. A l issue de ces résultats, un programme de surveillance et de prévention des infections en EHPAD (Programme Priam) a alors été commandé à l ORIG par le Ministère délégué aux personnes âgées. Ce projet de thèse se base sur ce programme de santé publique. Basé sur le programme Priam, le projet de thèse vise à : Estimer le poids des infections en EHPAD (Enquête nationale Priam). Rédiger des recommandations pour la prévention des infections en EHPAD (CFE Priam). Estimer la part évitable des infections (Étude Enlil)PARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Surveillance of occupational health in construction and civil-engineering workers handling engineered nanomaterials

Rationale: Entrusted by the Ministries of Health and of Labour, the French Public Health Agency have established, since 2014, the Epinano epidemiological surveillance system of workers potentially exposed in industries to engineered nanomaterials (ENMs) released during their synthesis or incorporation in matrices. The governmental national occupational health action plan 2016–2020 has dedicated a special attention to the question of ENMs exposure in workers in the construction and civil-engineering (CCE) sector. Thus, a steering committee was established to adapt the methodology to efficiently capture exposed workers on sites. Objectives: Beforehand, epidemiological and contextual components were collected in order to apprehend the methodological challenges in designing longitudinal studies on the topic of exposure to ENMs on CCE sites. Methods: A structured PubMed review and web-search of scientific and technical documents regarding ENM-based CCE products was undertaken, completed by in-depth experts’ interviews. Results: Three groups of methodological challenges were primarily identified: (i) Definition of the scope of the population, with involvement of enterprises of all sizes and activities; Heterogeneity of the population occurring on sites. (ii) Circumstances of exposures: No inventory identifying all the products incorporating ENMs; Lack of detailed information on product composition; Heterogeneity of ENMs incorporated in various matrices; Diversity of activities generating exposure variability in terms of product types, duration and intensity of exposure; Passive exposures of workers operating nearby activities involving ENMs and generating dust and aerosolisation; Possible interactions with other risk exposures in light of the multitude of chemicals used on construction sites. (iii) Defining the organizational arrangements to capture efficiently the study population and optimize data collection and monitoring procedures: Lability of the population, influenced by the duration of projects, a known high turnover generated mainly by the engagement of temporary, independent or foreign labourers, and intervention of multiple subcontractors; Regarding small, medium or micro-sized businesses, no service Health Safety Environment (HSE) and relocation of the occupational medicine. Conclusions: Implementing of such a study can be deeply influenced by the political context as well as the product marketing strategies along with the industrial secrecy. The use of ENM-based products would be probably increased in the current green economy context. This underscores the need to implement a specific surveillance system, despite the methodological complexity. Discussions are underway within the steering committee in order to find out strategies

Dispositif de surveillance EpiNano : inclusion des travailleurs manipulant des nanomatériaux manufacturés sur les chantiers du secteur du bâtiment et des travaux publics (BTP)

Le dispositif EpiNano pour la surveillance de l’état de santé des travailleurs potentiellement exposés aux nano-objets, leurs agrégats et agglomérats (NOAA) manufacturés a été déployé dès 2014 au niveau national. Dans le cadre du troisième plan santé travail, l’utilisation de produits à base de NOAA (nanoproduits) dans le BTP reçoit une attention particulière du fait de leur abondance croissante et une méconnaissance des risques potentiels. Un partenariat entre santé publique France et l’INRS, le CEA, l’Ineris et l’OPPBTP, est en cours de mise en place pour étendre EpiNano aux travailleurs du BTP

Occupational health and hazards in construction and civil-engineering workers handling engineered nanomaterials : challenges in designing epidemiological studies in france

Engineered nanomaterials (ENMs) induce groundbreaking impacts by endowing unique properties to materials. However, uncertainties remain on their biological aftereffects. Entrusted by health and labour ministries, the French Public Health Institute launched since 2014 the EpiNano epidemiological surveillance program of workers potentially exposed to ENMs. The 2016–2020 national occupational health (OH) action plan inscribed the ENMs topic as of priority, with an enlargement to the construction and civil-engineering (CCE) sector. A scientific consortium was therefore established in order elaborate a standardised methodology to identify ENMs-exposed CCE workers. A comprehensive, structured PubMed review and web-search of technical documents was undertaken, complemented by in-depth experts’ interviews to collect contextual information regarding CCE nanoproducts. Several methodological challenges were primarily revealed, pertaining primarily to : (i) Demarcating the target population: Involvement of a large number of companies (400,000) of all sizes and activities; Massive delegation to subcontractors; Heterogeneity of socioprofessional categories (from engineers to operators) and occupations (around 22); (ii) Unknown exposures’ circumstances: no CCE nanoproducts inventories neither detailed composition information; Unawareness of CCE actors of nanoproducts’ use; Heterogeneity of ENMs incorporated in various matrices (cement, coatings, paints…) with unknown ENM release/exposure potential; Potentially passive occupational exposures; Myriad of confusion factors with interactions with other risks at workplace; (iii) Capturing and following the eligible population: a complex topic to be addressed with a lot of pedagogy for adhering workers; epidemiological follow-up hampered by high turnovers, duration of construction sites and language barrier. Discussions are ongoing to overcome these methodological challenges. As a first step, an awareness campaign and the establishment of CCE nanoproducts’ inventory will be launched soon. An increase in CCE nanoproducts’ use is expected in the context of sustainable development and energy saving. This underscores the urgency to implement a specific surveillance system, by circumventing designing complexity

Les nanomatériaux manufacturés dans l'environnement professionnel : un aperçu de l'état de l'art

International audienceThe nanometric scale reveals unexpected properties of materials, and often completely different from those of the same materials at the micro- or macro-scales. Occupational exposures to engineered nanomaterials (ENMs) concern workers in research laboratories, manufacturing plants or sites of use of ENMs, the number of which remains unknown to date. Besides, significant quantities of ENMs are deployed yearly nationwide in a wide variety of sectors, according to R-Nano mandatory annual reporting register for ENMs (R-Nano Report). In parallel, several experimental studies, although scattered and still incomplete, sometimes even contradictory, suggest deleterious biological effects for certain families of ENMs. Uncertainties therefore remain on the risks potentially generated by some ENMs. Furthermore, metrological challenges persist for the assessment of exposures. However, despite this context of uncertainties, the prevention of occupational risks in workers exposed to ENMs is essential, and the existing regulations in terms of prevention of occupational risks remain applicable under the responsibility of employers. Professional national guidelines are made available to employers and occupational health services by the French National Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS) as well as the High Council for Public Health (HCSP). In addition, health monitoring (national EpiNano epidemiological surveillance system) is essential to provide convincing data concerning the health risks of workers potentially exposed to ENMs. This manuscript, written by a multidisciplinary group, provides an overview of the state of the art related to ENMs.Le passage de la matière à des dimensions nanométriques fait apparaître des propriétés inattendues et souvent totalement différentes de celles des mêmes matériaux à l’échellemicro- ou macroscopique. Les expositions professionnelles aux nanomatériaux manufacturés (NM) concernent des travailleurs dans les laboratoires de recherche, les usines de fabrication ou les sites d’utilisation de NM, dont le nombre reste à ce jour non déterminé. Par ailleurs,des quantités importantes de NM sont déployées annuellement en France dans des secteurs très variés selon le registre national de déclaration annuelle obligatoire des substances à l’état nanoparticulaire R-Nano. En parallèle, plusieurs études expérimentales, quoi qu’éparses, lacunaires, voire même contradictoires, suggèrent des effets biologiques délétères pour certaines familles de NM. Des incertitudes demeurent donc sur les risques engendrés par certains NM. De plus, des limites métrologiques persistent pour l’évaluation des expositions. Néanmoins,en dépit de ce contexte d’incertitudes, la prévention des risques professionnels chez les travailleurs exposés aux NM s’impose, et la réglementation existante en matière de prévention des risques professionnels reste applicable sous la responsabilité des employeurs. Des recommandations professionnelles sont mises à disposition des employeurs et des services de santé au travail par l’Institut national de recherche et de sécurité (INRS) ainsi que le Haut Conseil de Santé Publique (HCSP). En complément, la veille sanitaire (Dispositif national EpiNano) est incontournable pour fournir des données probantes concernant les risques pour la santé des travailleurs exposés aux NM. Ce manuscrit, rédigé par un groupe pluridisciplinaire, présente un aperçu de l’état de l’art relatif aux NM

Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.</p