Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Reconstruire un territoire moins vulnérable après une inondation : une fenêtre d’opportunité encore difficilement mobilisable

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Évolution de l’urbanisme et exposition au risque cyclonique à Saint-Martin de 1954 à 2017

International audienceHurricanes are common in the French West Indies and particularly on the island of Saint Martin. One can question the inability of society to face up to and recover from the consequences of these events. In this study, we show that between 1954 and 2017 (before Hurricane Irma), Saint Martin had to adapt to numerous constraints, some of which were far more important than hurricanes. In almost 70 years, the population density of the French part of Saint Martin increased from 75 inhab/km² to 668 inhab/km². The majority of this increase occurred in a five years period following the Pons law of 1986 which favoured tax breaks for real estate investment. More than 12 000 buildings were constructed in Saint Martin to welcome the new inhabitants of the island as well as tourists. Many neighbourhoods experienced significant growth which started in the late 1980's. However we observe differences in urban planning, a result of social and territorial segregation which exists on the island. On the one hand, there are private residences in affluent neighbourhoods, on the other hand working-class neighbourhoods with vulnerable dwellings. The effect of hurricanes on this society, which has been highly unequal since the 1960's up to the 1980's, is to reinforce inequalities. The fragile habitats of the poorest populations have been more deeply affected than the richest parts of the population which have been financially supported for reconstruction.Les ouragans sont relativement courants dans les Antilles et sur l'île de Saint-Martin en particulier. L'incapacité des sociétés à faire face à ce genre d'évènement et à s'en relever interroge. Dans cette étude, nous montrons que l'île de Saint-Martin a dû s'adapter entre 1954 et 2017 (avant l'ouragan Irma) à de nombreuses contraintes, dont certaines d'une ampleur bien plus importante que les ouragans. Ainsi en l'espace de presque 70 ans, la densité de population de la partie française de Saint-Martin est passée de 75 habitants par kilomètre carré à 668 habitants par kilomètre carré. La majeure partie de cette augmentation s'est produite en l'espace de 5 ans, suite à une loi de défiscalisation qui a favorisé l'investissement immobilier à partir de 1986 : la loi Pons. Plus de 12 000 bâtiments ont été construits à Saint-Martin pour accueillir les nouveaux habitants de l'île, mais aussi les touristes. De nombreux quartiers ont connu une croissance importante qui a débuté à la fin des années 1980. Cependant, on observe des spécificités dans l'urbanisme qui résultent de la très forte ségrégation sociale et territoriale qui règne sur l'île entre, d'un côté, les résidences privées des quartiers aisés et de l'autre les quartiers populaires, avec des habitations plus vulnérables. Les ouragans ont eu pour effet de renforcer les inégalités datant des années 1960-1980 en affectant plus particulièrement les habitats fragiles des populations les plus pauvres. Ces inégalités sont également accentuées par les sociétés qui accordent plus d'aides à la reconstruction aux personnes mieux insérées socialement

Quel relèvement territorial de Saint-Martin après l'ouragan Irma ?

International audienceAvec le concept de "build back better", l'ONU souligne l'importance de la phase de reconstruction suite à une catastrophe naturelle dans la gestion des risques naturels. Partant de l'hypothèse que les conséquences d'une catastrophe naturelle seraient l'occasion pour un territoire de mieux se reconstruire, cette étude vise à comprendre les processus de reconstruction en cours sur l'île de Saint-Martin 5 ans après l'ouragan Irma. Le relèvement de ce territoire semi-autonome est un défi majeur pour les autorités locales et pour l'État français. L'état actuel du relèvement post-catastrophe montre les difficultés à concilier les deux impératifs de "reconstruire vite" et "reconstruire mieux, dans un contexte de pression sociale, politique et médiatique. Notre analyse du relèvement moyen terme de Saint-Martin est basée sur trois facteurs : (1) le contexte historique et l'évolution de la construction des bâtiments au cours de ces 70 dernières années, (2) la réorganisation de la gouvernance de l’île, (3) la perception de la situation par la population. Cette approche interdisciplinaire originale de la phase de récupération post-catastrophe permet une meilleure compréhension de la complexité de cette période. Les résultats de cette étude et l'analyse croisée de ces trois méthodes mettent en évidence les liens de causalité entre la gouvernance de la reconstruction, le rétablissement psychosociologique des sinistrés, et l'histoire de l'urbanisation d'une île exposée aux risques naturels

Quel relèvement territorial de Saint-Martin 5 ans après l'ouragan Irma ?

International audienceLe projet Relev s’appuie sur une approche interdisciplinaire en intégrant des compétences en risques naturels (géographie, génie civil, géologie), aménagement du territoire (urbanisme, architecture) et sciences humaines (psychologie, sociologie, histoire), pour permettre d’améliorer la gestion de la reconstruction des territoires et des populations à la suite de catastrophes naturelles. Le projet se concentre sur le relèvement en cours des îles de Saint-Martin et Saint-Barthélemy, à la suite des ouragans Irma et Maria en septembre 2017. L’approche s’est articulée autour de deux temporalités d’étude pour mieux comprendre l’évolution des stratégies de développement de ces territoires exposés aux catastrophes naturelles : d’une part, une analyse historique des stratégies d'aménagement ante-Irma (de 1947 à 2017), d’autre part un retour d’expérience interdisciplinaire post-Irma (2017-2022) pour suivre la reconstruction de ces territoires. Ce retour d’expérience s’est focalisé plus particulièrement sur la reconstruction physique des infrastructures endommagées (bâtiments, infrastructures et réseaux techniques), le redémarrage des activités du tourisme et des PME en incluant les conséquences de la crise sanitaire de la Covid-19, le relèvement humain du point de vue individuel et collectif (état de stress, solidarité, vie sociale, autonomie économique, habitat, etc.) et enfin la réorganisation de la gouvernance locale. L’objectif est de s’appuyer sur une approche intégrée pour contribuer à l’émergence de nouveaux savoirs sur l’efficacité des stratégies de reconstruction post-catastrophe et de renforcer de manière cohérente la résilience des territoires face aux catastrophes naturelles, et par là même ; l’adaptation au changement climatique. Les enseignements du projet Relev documentent la gestion de la phase de reconstruction post-catastrophe à Saint-Martin et Saint-Barthélemy, et souligne la pertinence de planifier cette phase selon des modalités proches de celles déjà adoptées pour anticiper et préparer la gestion de crise. L'analyse interdisciplinaire a permis de mieux comprendre les liens de causalité entre la gouvernance de ces 2 îles, le relèvement psychosociologique des sinistrés, la reconstruction des infrastructures endommagées, la reprise des activités touristiques et l'histoire de l'urbanisation d'îles exposées aux risques naturels. En amont de futurs catastrophes, les enseignements du projet alimenteront également l’élaboration d’outils et de méthodes pour anticiper la gestion de la phase de reconstruction post-catastrophe

The impact of hurricanes on the island of Saint-Martin (French West Indies) from 1954 to 2017: how are our society changes?

International audienceNatural disasters lead to many victims and major damage in France and around the world. In 2017, Hurricane Irma hit the French islands of Saint-Martin and Saint-Barthélemy (West Indies), killing 11 people and causing more than €2 billion in insured damage. Ranked 5 in category on the Saffir-Simpson scale, with average winds of 287 km/h, this hurricane highlighted the vulnerability of our society to this type of phenomenon.One can question the inability of society to face up to and recover from the consequences of these events. In this sense, this work questions the adaptation of the island of Saint-Martin to hurricanes and its entire environment. We have chosen to focus on the evolution of this island over 65 years: from 1954 to 2017 (before Hurricane Irma). We mainly used aerial images of IGN (Institut National de l’Information Géographique et Forestière) available regularly since 1947. Among the elements that have served us to characterize this evolution, we have focused on land use (buildings, infrastructure and anthropization) and demographics.We show, in this study, that between 1954 and 2017 (before Hurricane Irma), Saint Martin had to adapt to numerous constraints, some of which were far more important than hurricanes. In 65 years, the population density of the French part of Saint Martin increased from 75 to 668 inhab/km². The majority of this increase occurred in a five year period following the Pons law of 1986 which favoured tax breaks for real estate investment. More than 12 000 buildings have been built in Saint Martin to welcome the new inhabitants of the island as well as tourists. Many neighbourhoods experienced significant growth which started in the late 80's. However we observe differences in urban planning, a result of social and territorial segregation which exists on the island. On the one hand, there are private residences in affluent neighbourhoods, on the other hand working-class neighbourhoods with vulnerable dwellings. The effect of hurricanes on this society, which has been highly unequal since the 1960's up to the 1980's, is to reinforce inequalities. The fragile habitats of the poorest populations have been more deeply affected than the richest parts of the population which have been financially supported for reconstruction

L’État et la politique de prévention des risques en phase post-catastrophe : le cas de la révision du PPRN de Saint-Martin

This work aims to analyse the conditions of application of a vulnerability reduction policy in the post-disaster phase, following Hurricane Irma (2017), on the island of Saint-Martin (French part). It focuses more specifically on the revision of the Natural Hazards Prevention Plan (hurricane hazard and marine submersion). The analysis is based in particular on a comparison of the process of drawing up previous regulatory documents on this territory, in order to highlight the difficulties of applying strategic planning to this very small island territory. More broadly, this work leads to a perspective on governance and the interplay of actors between the State and the local authority, and questions the management of the Natural Hazards Prevention Plan