A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders

Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA-DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes

Glutathione Deficiency in Cardiac Patients Is Related to the Functional Status and Structural Cardiac Abnormalities

International audienceBACKGROUND: The tripeptide glutathione (L-gamma-glutamyl-cysteinyl-glycine) is essential to cell survival, and deficiency in cardiac and systemic glutathione relates to heart failure progression and cardiac remodelling in animal models. Accordingly, we investigated cardiac and blood glutathione levels in patients of different functional classes and with different structural heart diseases. METHODS: Glutathione was measured using standard enzymatic recycling method in venous blood samples obtained from 91 individuals, including 15 healthy volunteers and 76 patients of New York Heart Association (NYHA) functional class I to IV, undergoing cardiac surgery for coronary artery disease, aortic stenosis or terminal cardiomyopathy. Glutathione was also quantified in right atrial appendages obtained at the time of surgery. RESULTS: In atrial tissue, glutathione was severely depleted (-58%) in NYHA class IV patients compared to NYHA class I patients (P = 0.002). In patients with coronary artery disease, this depletion was related to the severity of left ventricular dysfunction (P = 0.006). Compared to healthy controls, blood glutathione was decreased by 21% in NYHA class I patients with structural cardiac disease (P<0.01), and by 40% in symptomatic patients of NYHA class II to IV (P<0.0001). According to the functional NYHA class, significant depletion in blood glutathione occurred before detectable elevation in blood sTNFR1, a marker of symptomatic heart failure severity, as shown by the exponential relationship between these two parameters in the whole cohort of patients (r = 0.88). CONCLUSIONS: This study provides evidence that cardiac and systemic glutathione deficiency is related to the functional status and structural cardiac abnormalities of patients with cardiac diseases. These data also suggest that blood glutathione test may be an interesting new biomarker to detect asymptomatic patients with structural cardiac abnormalities

Schizophrenia Bulletin Open

Treatment-resistant schizophrenia (TRS) affects around 30% of patients with schizophrenia (SZ) resulting in poor functioning, relapses, and reduced quality of life. Convergent findings show that inflammation could contribute to resistance. We thus search for immune signatures of patients with TRS/ultra TRS (UTRS) in a sample of community-dwelling outpatients with SZ. In total, 195 stabilized SZ patients (mean age = 31.2 years, 73% male gender) were consecutively included in the network of the FondaMental Expert Centers for Schizophrenia in France and received a thorough clinical assessment. At inclusion, psychotic symptomatology was evaluated by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Circulating serum/plasma levels of a large panel of markers reflecting the main inflammatory pathways were evaluated. TRS was defined by current treatment by clozapine (CLZ) and UTRS by current CLZ treatment + PANSS total score ≥ 70. The frequency of TRS and UTRS patients was, respectively, 20% and 7.7% and was defined using multivariable analysis elevated by high levels of interleukin (IL)-12/IL-23p40, IL-17A, IL-10, and beta 2 microglobulin (B2M) and IL-12/IL-23p40, IL-17A, IL-6, IL-10, IFNγ, and B2M, respectively. These observations suggest that resistance and ultra resistance to CLZ treatment are underpinned by pro-inflammatory molecules mainly belonging to the T helper 17 pathway, a finding making sense given the interplay between inflammation and antipsychotic treatment responses. If confirmed, our findings may allow us to consider IL-23/IL-17 pathway as a therapeutic target for patients with resistance to antipsychotics.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte

[The Clinical Investigation Centers in France: Whatzat? What for? How does it work?]

International audienceFor the last 15 years, French university-affiliated hospitals have dramatically modified how biomedical research is conducted in France. Multidisciplinary and technically complex research projects are increasingly difficult to conduct in clinical units. To ensure quality, good clinical practice, and security, platforms dedicated to clinical research with specific staff have been implanted. These units, called Clinical Investigation Centers (CICs), are open to academic and industrial investigators working in the medical fields involving patients and healthy volunteers. The CICs' activities are always closely related to the university hospital research programs and can also serve as a tool for locally implanted clinical and fundamental research teams (INSERM). Nowadays, clinical research requires specific tools and platforms. To enhance French university hospital research efficiency and provide a more open research environment, all investigators, on-site as well as from other institutions, are invited to use these cohesive research facilities and skills to conduct protocols that are fully adapted to their needs in optimal conditions of professional clinical research

Facteurs modulateurs du phénotype des cardiopathies (approche expérimentale)

La sévérité du phénotype des cardiomyopathies peut être modulée par de multiples facteurs indépendamment de son étiologie. Le terrain génétique affecte le phénotype en raison de l'existence de polymorphismes entre les individus au sein de gènes dits modificateurs. Un des principaux résultats de ce travail a été de localiser dans le génome murin plusieurs loci influençant le phénotype dans un modèle expérimental d'insuffisance cardiaque. Par ailleurs, nous avons montré qu'un phénomène physiologique comme le vieillissement modifie la réponse des cardiomyocytes à une stimulation alpha-1 adrénergique. La réduction de la transitoire calcique observée dans le cœur sénescent pourrait être liée à un défaut de translocation de la Protéine Kinase C. Enfin, un certain nombre de facteurs environnementaux, comme la teneur en sel de l'alimentation, modifie également le phénotype cardiaque. Ce travail a montré que l'activation du système rénine-angiotensine tissulaire joue un rôle clef dans ce processus.The phenotype of the cardiomyopathies can be modified by several factors independently of its etiology. The genetic background affects the phenotype due to polymorphisms between patients within modifier genes. One of the main results of this work was to localize within the genome the loci modifying the phenotype in an experimental model of heart failure. In addition, we showed that a physiological factor such as ageing modifies the cardiomyocytes response to an alpha-1 adrenergic stimulation. The decrease of calcium transient observed in the aged heart could be related to a lack of translocation of the protein kinase C. Finally, some environmental factors such as salt intake modify heart phenotype. We showed that activation of the cardiac rennin-angiotensin system plays a key role in this process.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

ANALYSE DESCRIPTIVE DE LA MORTALITE DES PATIENTS HOSPITALISES EN CARDIOLOGIE (EXPERIENCE DE LA FEDERATION DE CARDIOLOGIE DE L'HOPITAL HENRI MONDOR)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Rôle du monoxyde d’azote dans l’insuffisance cardiaque

La démonstration des effets bénéfiques des donneurs de monoxyde d’azote (NO) dans l’insuffisance cardiaque aiguë a été à la base du développement des vasodilatateurs dans le traitement de l’insuffisance cardiaque chronique. Cependant, les mécanismes d’action du NO dans ce cadre sont complexes et demeurent l’objet de nombreux débats. Le NO paraît impliqué dans l’anomalie de la vasodilatation endothélium-dépendante du fait de la réduction de l’expression de la NO synthase endothéliale dans la paroi vasculaire. Au niveau cardiaque, sous l’influence des cytokines, il existe une induction des NO synthases qui engendre une augmentation de la synthèse de NO par le myocarde insuffisant. Cette synthèse excessive, associée à une surproduction d’anions superoxydes, entraîne des effets délétères qui limitent les effets inotropes positifs des catécho- lamines et engendrent un effet pro-apoptotique favorisant l’altération de la fonction ventriculaire gauche. La place des dérivés nitrés dans l'insuffisance cardiaque chronique demeure controversée, même s’ils améliorent la précharge et potentiellement les symptômes. D’autres molécules comme les IEC apparaissent agir en partie via le NO, au travers de l’accumulation des kinines. En augmentant l’expression vasculaire de la NO synthase endothéliale, la rééducation cardiaque permet d’améliorer la tolérance à l’effort des insuffisants cardiaques

Risk of major adverse cardiovascular events in patients initiating biologics/apremilast for psoriatic arthritis: a nationwide cohort study

International audienceAbstract Objective Several biological DMARDs (bDMARDs) have demonstrated anti-inflammatory effects in PsA. However, their comparative cardiovascular safety profiles remain unknown. We evaluated the risk of major adverse cardiovascular events (MACEs) in PsA patients on therapy with different classes of bDMARDs and apremilast. Methods This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database. All adults with PsA who were new users of bDMARDs/apremilast (neither in the year before the index date) during 2015–19 were included. Patients with previous cardiovascular diseases were excluded. End of follow-up was 31 December 2019. The primary endpoint was an occurrence of MACEs in a time-to-event analysis with propensity score-weighted Cox and Fine–Gray models. Results Between 2015 and 2019, we included 9510 bDMARD new users [mean age 48.5 (s.d. 12.7) years; 42% men], including 7289 starting a TNF inhibitor, 1058 an IL-12/23 inhibitor and 1163 an IL-17 inhibitor, with 1885 apremilast new users [mean age 54.0 (s.d. 12.5) years; 44% men]. MACEs occurred in 51 (0.4%) patients. After propensity score weighting, the risk of MACEs was significantly greater with IL-12/23 (weighted hazard ratio 2.0, 95% CI 1.3, 3.0) and IL-17 (weighted hazard ratio 1.9, 95% CI 1.2, 3.0) inhibitors than TNF inhibitors, with no significant increased risk with apremilast (weighted hazard ratio 1.3, 95% CI 0.8, 2.2). Similar results were observed with the Fine–Gray competing risks survival model. Conclusion Analysis of a large database revealed a small overall number of MACEs, and the risk of MACEs was greater for PsA new users of IL-12/23 and IL-17 vs TNF inhibitors

Factors associated with remission at 5-year follow-up in recent-onset axial spondyloarthritis: results from the DESIR cohort

International audienceAbstract Objective The factors contributing to long-term remission in axial SpA (axSpA) are unclear. We aimed to characterize individuals with axSpA at the 5-year follow-up to identify baseline factors associated with remission. Methods We included all patients from the DESIR cohort (with recent-onset axSpA) with an available Ankylosing Spondylitis Disease Activity Score–CRP (ASDAS-CRP) at 5-year follow-up. Patients in remission (ASDAS-CRP &lt; 1.3) were compared with those with active disease by demographic, clinical, biological and imaging characteristics. A logistic model stratified on TNF inhibitor (TNFi) exposure was used. Results Overall, 111/449 patients (25%) were in remission after 5 years. Among those never exposed to TNFi, 31% (77/247) were in remission compared with 17% (34/202) of those exposed to TNFi. Patients in remission after 5 years were more likely to be male, HLA-B27+, have a lower BMI, and a higher education level. Baseline factors associated with 5-year remission in patients never exposed to TNFi included lower BASDAI [adjusted odds ratio (ORa) 0.9, 95% CI: 0.8, 0.9) and history of peripheral arthritis (ORa 2.1, 95% CI: 1.2, 5.3). In those exposed to TNFi, remission was associated with higher education level (ORa 2.9, 95% CI: 1.6, 5.1), lower enthesitis index (ORa 0.8, 95% CI: 0.7, 0.9), lower BASDAI (ORa 0.9, 95% CI: 0.9, 0.9) and lower BMI (ORa 0.8, 95% CI: 0.7, 0.9). Conclusion This study highlights the difficulty in achieving 5-year remission in those with recent-onset axSpA, especially for the more active cases, despite the use of TNFi. Socio-economic factors and BMI are implicated in the outcome at 5 years