Polygenic risk scores have high diagnostic capacity in ankylosing spondylitis

We would like to thank all participating subjects with AS and healthy individuals who provided the DNA and clinical information necessary for this study. The TASC study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915, R01-AR046208. Funding was also received from the University of Texas Health Science Center at Houston CTSA grant UL1RR02418, Cedars-Sinai GCRC grant MO1-RR00425, Intramural Research Program, NIAMS/NIH, and Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis Research UK (Grants 19536 and 18797), by the Wellcome Trust (grant number 076113), and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (Theme Code: A91202). JZB was funded by a grant from the Zhejiang Provincial Natural Science Foundation of China (LD18H120001LD). The New Zealand data was derived from participants in the Spondyloarthritis Genetics and the Environment Study (SAGE) and was funded by The Health Research Council, New Zealand. HX was funded by the National Natural Science Foundation of China (Grant 81430031) and China Ministry of Science and Technology (973 Program of China 2014CB541800). We acknowledge the Understanding Society: The UK Household Longitudinal Study. This is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen and the genome-wide scan data were analysed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website https: www.understandingsociety.ac.uk/. French sample collection was performed by the Groupe Française d’Etude Génétique des Spondylarthrites, coordinated by Professor Maxime Breban and funded by the Agence Nationale de Recherche GEMISA grant reference ANR-10-MIDI-0002. We acknowledge and thank the TCRI AS Group for their support in recruiting patients for the study (see below). The authors acknowledge the sharing of data and samples by the BSRBR-AS Register in Aberdeen. Chief Investigator, Prof Gary Macfarlane and Dr. Gareth Jones, Deputy Chief Investigator created the BSRBR-AS study which was commissioned by the British Society for Rheumatology, funded in part by Abbvie, Pfizer and UCB. We are grateful to every patient, past and present staff of the BSRBR-AS register team and to all clinical staff who recruited patients, followed them up and entered data – details here: https://www.abdn.ac.uk/iahs/research/epidemiology/spondyloarthritis.php#panel1011. The QIMR control samples were from parents of adolescent twins collected in the context of the Brisbane Longitudinal Twin Study 1992–2016, support by grants from NHMRC (NGM) and ARC (MJW). We thank Anjali Henders, Lisa Bowdler, Tabatha Goncales for biobank collection and Kerrie McAloney and Scott Gordon for curating samples for this study. MAB is funded by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship (1024879), and support for this study was received from a National Health and Medical Research Council (Australia) program grant (566938) and project grant (569829), and from the Australian Cancer Research Foundation and Rebecca Cooper Medical Research Foundation. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for patient recruitment was provided by the National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and an unrestricted educational grant from Abbott Laboratories. This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.Peer reviewedPublisher PD

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The emergence of sedentary behaviour physiology and its effects on the cardiometabolic profile in young and older adults

It has recently emerged that sedentary behaviour is independent of a lack of physical activity as individuals can be sufficiently active, based on the recommended physical activity guidelines, but also spend the majority of their waking hours engaging in sedentary behaviour. Individuals who follow this pattern of physical activity and sedentary behaviour are known as ‘active couch potatoes’. Sedentary behaviour has been found to have detrimental effects on cardiometabolic markers associated with cardiovascular disease. Since the positive effects of moderate-to-vigorous intensity physical activity do not necessarily negate the deleterious effects of sedentary behaviour on cardiometabolic markers, it is postulated that engaging in light physical activity is an intervention that will successfully reduce levels of sedentary behaviour and may hence improve health markers of quality of life. We propose that such lifestyle changes may be particularly relevant to older populations as these engage in sedentary behaviour for the majority of their waking hours, thereby adding to the negative aging effect on cardiometabolic markers

Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. / Methods: A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering. / Results: Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. / Conclusion: Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis

Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis

Objectives: To evaluate construct validity, interpretability, reliability and responsiveness as well as determination of cut-off points for good and poor health within the original English version and the 18 translations of the disease-specific Assessment of Spondyloarthritis international Society Health Index (ASAS HI) in 23 countries worldwide in patients with spondyloarthritis (SpA). Methods: A representative sample of patients with SpA fulfilling the ASAS classification criteria for axial (axSpA) or peripheral SpA was used. The construct validity of the ASAS HI was tested using Spearman correlation with several standard health outcomes for axSpA. Test–retest reliability was assessed by intraclass correlation coefficients (ICCs) in patients with stable disease (interval 4–7 days). In patients who required an escalation of therapy because of high disease activity, responsiveness was tested after 2–24 weeks using standardised response mean (SRM). Results: Among the 1548 patients, 64.9% were men, with a mean (SD) age 42.0 (13.4) years. Construct validity ranged from low (age: 0.10) to high (Bath AnkylosingSpondylitisFunctioning Index: 0.71). Internal consistency was high (Cronbach’s α of 0.93). The reliability among 578 patients was good (ICC=0.87 (95% CI 0.84 to 0.89)). Responsiveness among 246 patients was moderate-large (SRM=−0.44 for non-steroidal anti-inflammatory drugs, −0.69 for conventional synthetic disease-modifying antirheumatic drug and −0.85 for tumour necrosis factor inhibitor). The smallest detectable change was 3.0. Values ≤5.0 have balanced specificity to distinguish good health as opposed to moderate health, and values ≥12.0 are specific to represent poor health as opposed to moderate health. Conclusions:  The ASAS HI proved to be valid, reliable and responsive. It can be used to evaluate the impact of SpA and its treatment on functioning and health. Furthermore, comparison of disease impact between populations is possible

Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ~3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology

Challenges and approaches for the development of safer immunomodulatory biologics

Immunomodulatory biologics are a class of agents that render their therapeutic effect via modulating or harnessing immune responses. Despite their therapeutic efficacy in complex conditions including cancer and autoimmune diseases, there is a growing concern about their unwanted adverse events including infections, malignancy, cytokine release syndromes, anaphylaxis, hypersensitivity and immunogenicity. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the key approaches to understand, predict and mitigate adverse events associated with their use