Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Influence of TYK2 in systemic sclerosis susceptibility: A new locus in the IL-12 pathway

Objectives TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc. Methods This study comprised a total of 7103 patients with SSc and 12â €..220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-Analyses were performed using the inverse variance method. Results Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10 â '13, OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10 â '3, OR=0.80; p=1.27×10 â '3, OR=0.59; p=2.63×10 â '5, OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants. Conclusions We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology

Brief Report: IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc–RA loci through an interdisease meta–genome-wide association (meta-GWAS) strategy. Methods: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case–control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10−6) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc–RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10−12). Analysis of the biologic relevance of the known SSc–RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci

Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression.Pathophysiology and treatment of rheumatic disease

IRF4 Newly Identified as a Common Susceptibility Locus for Systemic Sclerosis and Rheumatoid Arthritis in a Cross-Disease Meta-Analysis of Genome-Wide Association Studies

Autoría conjunta: Spanish Scleroderma GrpObjective. Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. Methods. The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results. This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P<5 x 10(-6)) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (P-combined=3.29 x 10(-12)). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion. This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.Supported by a grant from the Ministerio de Educacion, Cultura y Deporte through the program FPU (to Dr. Lopez-Isac), grant 115565 from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (ref. no. 115565) and BIO-1395 from the Junta de Andalucia, grant PI-0590-2010 from the Consejeria de Salud y Bienestar Social, Junta de Andalucia, Spain (to Dr. Ortego-Centeno), a VIDI laureate from the Dutch Association of Research and Dutch Arthritis Foundation (to Dr. Radstake), and grant SAF2012-34435 from the Spanish Ministry of Economy and Competitiveness (to Dr. J. Martin). Dr. Assassi's work was supported by grants KL2-RR-024149-04 and K23-AR-061436 from the NIH, grant 3-UL1-RR-024148 from the NIH National Center for Research Resources, and grant U01-1U01AI09090 from the NIH National Institute of Allergy and Infectious Diseases. Dr. Mayes' work was supported by grant P50-AR-054144 from the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Centers of Research Translation, grant N01-AR-0-2251 from the NIAMS SSc Family Registry and DNA Repository, grant PR-1206877 from the Department of Defense, and grant R01-AR-055258 from the NIAMS.Peer reviewe

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p

OP0014 HLA ASSOCIATIONS IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS ASSOCIATED UVEITIS AND CLINICAL SUBTYPES

Background:Juvenile idiopathic arthritis (JIA) is a childhood onset rheumatic disease which is classified into seven different clinical subtypes based upon the ILAR classification criteria. The most common extra articular manifestation of JIA is its associated uveitis (JIAU); particularly chronic anterior uveitis (CAU). Uveitis is a serious complication with the potential to lead to visual impairment and blindness. The rheumatoid factor negative polyarthritis and oligoarthritis ILAR subtypes, often referred to as the “polygo” subgroup, are at a higher risk for developing JIAU, with up to 30% of polygos afflicted by CAU. The HLA region has long been reported as a genetic risk factor for JIA susceptibility, with evidence suggesting that different amino acids of HLA genes infer risk to different JIA subtypes.Objectives:Investigate the association of amino acids and genetic variants in the HLA region with susceptibility to JIAU and the ILAR clinical subtypes.Methods:Samples were genotyped using the Illumina Infinium CoreExome and Infinium Onmiexpress arrays. Samples were excluded based on &lt;98% call rate, discrepancy between genetically inferred sex and database records, inferred relatedness (identify-by-descent) and ancestral outliers based on principal component analysis (PCA). SNPs were excluded based on &lt;0.01 minor allele frequency (MAF), and call rate &lt;98%. SNP2HLA was used to impute HLA amino acids, SNPs and alleles. Analysis was then executed on markers with an information score &gt;0.9 and MAF &gt;.01 using logistic regression or an omnibus test for multiallelic markers, including 3 PCs as covariates. Independent associations were identified using forward stepwise logistic regression including previously identified variants as covariates. Comparison of regression models was performed using a likelihood ratio test (LRT).Results:We analysed 7425 markers within the HLA region in 450 JIAU and 2024 JIA cases without uveitis. The most significant association was to amino acid positions 13 of HLA-DRB1 (p=2.9×10-30). Conditional analysis on DRB1 position 13 revealed an independent signal at DRB1 position 67 (p=2.4×10-6). Conditioning on all DRB1 alleles revealed an independent signal at HLA-DPB1 position 69 (p=5.3×10-7). As expected, ILAR subtype was found to be associated with JIAU (p=1.58×10-6). We used LRT to test if genetics provided further information above ILAR subtype alone and found that including residues at DRB1 position 13 significantly improved the fit of a model based on ILAR subtype alone (LRT p = 3.6×10-27). The reciprocal analysis, adding ILAR subtype to a model based on DRB1 position 13 alone, did not significantly improve the fit of a model (LRT p=0.83). Exploring associations in the polygo subgroup (n=1646) we found significant associations to the three previously described amino acids and JIAU (DRB1 position 13 p=3.4×10-20, DRB1 position 67 p=3.3×10-4, DPB1 position 69 p=2.2×10-6).Conclusion:This is largest analysis of HLA markers in JIAU patients to date and we identify two independent associations to amino acids in HLA-DRB1 and a further independent association to HLA-DPB1. This analysis demonstrates that including data on genetic risk factors adds further information to that captured by ILAR subtype alone. It also reveals that the previously validated associations at position 13 of HLA-DRB1 are also correlated with JIAU in the polygo subtype suggesting that genetic risk factors will help refine risk within clinical subtypes. Conditioning on DRB1 alleles reveals that the secondary independent DRB1 position 69 association is also strongly associated in the polygo subset of this cohort. Together these results highlight the potential future use of genetics risk factors for risk classification for uveitis in patients with JIADisclosure of Interests:None declared</jats:sec

The ReCaPTa study - a prospective out of hospital cardiac arrest registry including multiple sources of surveillance for the study of sudden cardiac death in the Mediterranean area

Background: Cardiovascular diseases are one of the leading causes of death in the industrialized world. Sudden cardiac death is very often the first manifestation of the disease and it occurs in the prehospital setting. The determination of the sudden cardiac death phenotype is challenging. It requires prospective studies in the community including multiple sources of case ascertainment that help to identify the cause and circumstances of death. The aim of the Clinical and Pathological Registry of Tarragona (ReCaPTa) is to study incidence and etiology of Sudden Cardiac Death in the Tarragona region (Catalonia, Spain). Methods: ReCaPTa is a population-based registry of OHCA using multiple sources of surveillance. The population base is 511,662. This registry is compiled chronologically in a relational database and it prospectively contains data on all the OHCA attended by the EMS from April 2014 to April 2017. ReCaPTa collects data after each emergency medical assistance using an online application including variables of the onset of symptoms. A quality control is performed and it permits monitoring the percentage of cases included by the emergency crew. Simultaneously, data from the medico-legal autopsies is taken from the Pathology Center of the area. All the examination findings following a specific protocol for the sudden death study are entered into the ReCaPTa database by one trained person. Survivors admitted to hospital are followed up and their clinical variables are collected in each hospital. The primary care researchers analyze the digital clinical records in order to obtain medical background. All the available data will be reviewed after an adjudication process with the aim of identifying all cases of sudden cardiac death. Discussion: There is a lack of population-based registries including multiple source of surveillance in the Mediterranean area. The ReCaPTa study could provide valuable information to prevent sudden cardiac death and develop new strategies to improve its survival.</p