Association of Genetic Variants in NUDT15 with Thiopurine-Induced Myelosuppression in Patients with Inflammatory Bowel Disease

Funding Information: reported serving as a consultant for AbbVie UK; receiving honoraria from Falk and AbbVie UK; receiving grants from Crohn’s & Colitis UK and Tillott’s Pharmaceuticals; having a fellowship from the UK National Institute for Health Research; and receiving travel reimbursement from Merck Sharp & Dohme and Norgine. Dr Heap reported receiving travel reimbursement from AbbVie; and being a current employee of AbbVie and owning stock in the company. Dr Andersen reported receiving personal fees from Merck Sharp & Dohme and Janssen. Dr Ananthakrishnan reported receiving a grant from Pfizer; and receiving personal fees from Takeda. Dr Beaugerie reported receiving advisory board fees from Allergan, Janssen, and Pfizer; receiving a grant from Hospira; and receiving grants and honoraria from AbbVie, Merck Sharp & Dohme, Ferring, Takeda, and Tillott’s Pharmaceuticals. Dr Cummings reported receiving personal fees from AbbVie, Takeda, Biogen, Janssen, Merck Sharp & Dohme, Amgen, Hakim Pharmaceuticals, and Pfizer/Hospira; and receiving grants from Takeda, Biogen, AstraZeneca, and Pfizer/Hospira. Dr Halfvarson reported receiving personal fees from AbbVie, Hospira, Janssen, Medivir, Merck Sharp & Dohme, Pfizer, RenapharmaVifor, Takeda, Tillott’s Pharmaceuticals, Celgene, Sandoz, and Shire; and receiving grants from Janssen, Merck Sharp & Dohme, and Takeda. Dr Hart reported receiving advisory board fees from AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Janssen, Merck Sharp & Dohme, Pfizer, Shire, and Takeda; receiving honoraria from Falk and Ferring; and receiving a grant from Takeda. Dr Irving reported receiving personal fees from Janssen, AbbVie, Takeda, Ferring, Pfizer, Lilly, Merck Sharp & Dohme, Samsung, and Sandoz; and receiving grants from Takeda and Merck Sharp & Dohme. Dr Lindsay reported receiving advisory board fees from Atlantic Health, AbbVie UK/global, Merck Sharp & Dohme, Shire UK, Vifor Pharma, Ferring International, Celltrion, Takeda, Napp, Pfizer, and Janssen; serving as a consultant for AbbVie UK/global, Takeda, and Pfizer; receiving grants from Shire UK, AbbVie UK/global, Warner Chilcott, Funding Information: Takeda, Hospira, Ferring International, and Merck Sharp & Dohme; receiving honoraria from Takeda, Cornerstones US, Tillott’s Pharmaceuticals, Napp, Shire International, Janssen, AbbVie, and Pfizer; and receiving travel reimbursement from AbbVie UK, Merck Sharp & Dohme, Warner Chilcott, Takeda, and Shire International. Dr McGovern reported receiving grants from the National Institutes of Health, Helmsley Charitable Trust, and Janssen; and serving as a consultant for Pfizer, Q Biologics, Cidara, Gilead, and Janssen. Dr Seksik reported receiving advisory board fees from Astellas; receiving honoraria from Takeda, AbbVie, and Ferring; and receiving grants from Merck Sharp & Dohme and Biocodex. Dr Sokol reported receiving grants from Biocodex, Danone, and BiomX; serving as a consultant for Enterome, Takeda, AbbVie, Roche, Amgen, Danone, BiomX, Ferring, Bristol-Myers Squibb, Astellas, Merck Sharp & Dohme, Novartis, Tillott’s Pharmaceuticals, and Biose; and being the co-founder of Nextbiotix. Dr Annese reported receiving advisory board fees from Takeda, AbbVie, and Medtronic; and receiving honoraria from Janssen, Takeda, AbbVie, and Medtronic. Dr Weersma reported receiving grants from Takeda, Ferring, and Tramedico; and receiving personal fees from AbbVie. Dr Goodhand reported receiving honoraria from Falk, AbbVie, and Shield Therapeutics. Dr Kennedy reported serving as a consultant for Falk; receiving honoraria from Falk, Allergan, Pharmacosmos, and Takeda; and being a deputy editor of Alimentary Pharmacology & Therapeutics. Dr Ahmad reported receiving unrestricted grants, advisory board fees, speaker honoraria, and support to attend international meetings from AbbVie, Merck Sharp & Dohme, Janssen, Takeda, Ferring, Tillott’s Pharmaceuticals, Ferring, Pfizer, Napp, Celltrion, and Hospira. No other disclosures were reported. Funding Information: Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California), Alistair McNair, PhD (Queen Elizabeth Hospital, London, UK), Anita Modi, MD (Luton and Dunstable University Hospital, Luton, UK), Kevin Monahan, PhD (West Middlesex University Hospital, Middlesex, UK), Alex Moran, MD (Northern Devon Healthcare Trust, Barnstaple, UK), Mary-Anne Morris, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Marianne Mortimore, MBBS (Mater Research Institute, University of Queensland, South Brisbane, Australia), Craig Mowat, MD (Ninewells Hospital, NHS Tayside, Dundee, UK), Rafeeq Muhammed, MD (Birmingham Children's Hospital, Birmingham, UK), Charles D. R. Murray, PhD (Royal Free Hospital, Royal Free London NHS Foundation Trust, London, UK), Hanlie Olivier (IBD Pharmacogenetics Group, University of Exeter, Exeter, UK), Timothy R. Orchard, DM (Imperial College Healthcare NHS Trust, London, UK), Simon Panter, MD (South Tyneside District Hospital, South Tyneside, UK), Vinod Patel, MBBS (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rosemary Phillips, MD (Princess Alexandra Hospital, Essex, UK), Neeraj Prasad, MSc (Wrightington Hospital, Wrightington, UK), Cathryn Preston, MBChB (Bradford Royal Infirmary, Bradford, UK), Graham Radford-Smith, PhD (Royal Brisbane and Women’s Hospital, Brisbane, Australia), Praveen Rajasekhar, MD (Northumbria NHS Trust, Tyne and Wear, UK), Dipak Roy, PhD (Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK), Rebecca Saich, PhD (Basingstoke and North Hampshire Hospital, Basingstoke, UK), Jack Satsangi, PhD (Western General Hospital, NHS Lothian, Edinburgh, UK), Stefan Schreiber, PhD (Kiel University, Kiel, Germany), Sandip Sen, MD (Royal Stoke University Hospital, Stoke-on-Trent, UK), Neil Shah, MD (Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK), Richard Shenderay, MBBS (Airedale NHS Foundation Trust, Keighley, UK), Acuth Shenoy, MD (Colchester Hospital University NHS Foundation Trust, Colchester, UK), James Shutt, DM (Dorset County Hospital NHS Foundation Trust, Dorchester, UK), Mark Silverberg, PhD (Mount Sinai Hospital, Toronto, Ontario, Canada), Alison Simmons, PhD (Oxford University Hospitals, Oxford, UK), Jonathan Simmons, DM (Royal Berkshire Hospital, Royal Berkshire NHS Foundation Trust, Reading, UK), Salil Singh, PhD (Bolton NHS Foundation Trust, Bolton, UK), Malcolm Smith, MBChB (Aberdeen Royal Infirmary, Aberdeen, UK), Mark Smith, MD (Shrewsbury and Telford Hospital NHS Trust, Shrewsbury, UK), Melissa Smith, MB (Royal Sussex County Hospital, Brighton, UK), Jonathon A. Snook, DPhil (Poole Hospital NHS Foundation Trust, Poole, UK), Sunil Sonwalker, MD (Calderdale Royal Hospital, Halifax, UK), Christine R. Stevens, PhD (Broad Institute, Harvard University, Cambridge, Massachusetts), Giacomo Sturniolo, PhD (Univerita di Padova, Padova, Italy), Sreedhar Subramanian, MD (Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK), Amanda Thomas, MBBS (Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK), Mark Tighe, BM (Poole Hospital NHS Foundation Trust, Poole, UK), Franco Torrente, MD (Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), Mark Tremelling, MD (Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK), Epameinondas Tsianos, PhD (University Hospital of Ioannina, Ioannina, Greece), Deven Vani, MD (Mid Yorkshire Hospitals NHS Trust, Wakefield, UK), Alissa Walsh, MBBS (St Vincent’s Hospital, Sydney, Australia), Gillian Watermeyer, MBChB (Groote Schuur Hospital, Cape Town, South Africa), David Watts, MBChB (Forth Valley Royal Hospital, Larbert, UK), Gill Watts, MD (Wythenshawe Hospital, South Manchester, UK), Sean Weaver, PhD (Royal Bournemouth General Hospital, Bournemouth, UK), Emma Wesley, MBBS (Musgrove Park Hospital, Taunton and Somerset NHS Hospitals, Taunton, UK), Anne Willmott, MBChB (Leicester Royal Infirmary-Paediatric, Leicester, UK), Karen Yearsley, BM (Nevill Hall Hospital, Abergavenny, UK), Veena Zambar, MBBS (Leeds General Infirmary, Leeds, UK), and Sebastian Zeissig, MD (University Medical Center Schleswig-Hostein, Kiel, Germany). These individuals identified and recruited patient s to the study and provided comments on a draft of the manuscript. Funding Information: Adverse Events Consortium funded the sample collection and genotyping at the Broad Institute. The UK National Institute for Health Research provided research nurse support to facilitate recruitment at all UK research sites. Crohn’s & Colitis UK and forCrohns provided funding support and publicized this study to their members. The Exeter National Institute for Health Research Clinical Research Facility provided DNA storage and management. Institutional strategic support award WT097835MF from Wellcome Trust supported the management of the study. Samples from Cedars-Sinai were collected and processed through the MIRIAD biobank that was funded by grant P01DK046763 from the National Institutes of Health. Publisher Copyright: © 2019 American Medical Association. All rights reserved.IMPORTANCE Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). OBJECTIVE To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). DESIGN, SETTING, AND PARTICIPANTS Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. EXPOSURES Genetic variants associated with TIM. MAIN OUTCOMES AND MEASURES Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 x 10(9)/L or less or a decline in absolute neutrophil cell count to 1.0 x 10(9)/L or less leading to a dose reduction or drug withdrawal. RESULTS Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 x 10(-9)). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 x 10(-8)), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 x 10(-7)) of TIM, independent of TPMT genotype and thiopurine dose. CONCLUSIONS AND RELEVANCE Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.Peer reviewe

The Effects of a Culturally Sensitive, Empowerment-Focused, Community-Based Health Promotion Program on Health Outcomes of Adults with Type 2 Diabetes

Th e purpose of the present study was to test the effects of a culturally sensitive, health empowerment- focused, community- based health promotion program tailored to adult patients with type 2 diabetes on these patients’ body mass index (BMI), blood pressure, and self- reported blood glucose levels, treatment adherence, and stress levels. Study participants (N = 130) consisted mostly of African Americans (70%) and Hispanic/ Latinos (22.3%) who were divided almost evenly between an intervention group and wait- list control group. Th e tested health promotion program is informed by Health Self- Empowerment Theory. At post- test, program participants in the intervention group as compared to those in the control group demonstrated significantly lower levels of BMI, diastolic blood pressure, and physical stress. Implications of these study findings for future similar programs and research are discussed

Coping Using Sex, Health-Related Behaviors, and Mental Health During COVID-19 Lockdown in the UK

Background: Peoples' sexual behaviors have changed during the period of enforced COVID-19 social distancing, in some cases, to cope with negative feelings during lockdown. Research on coping using sex is relatively restricted to samples of men with a history of sexual offending, and it is unknown whether coping using sex is associated with health-related behaviors and mental health in the general population. Aim: We examined if coping using sex before and during lockdown was associated with adverse outcomes (i.e., self-perceived reduction in health-related behaviors and mental health) in a community sample. Hypotheses: We hypothesized that participants who reported greater use of sex to cope in the weeks preceding lockdown would show a greater decline in health-related behaviors and mental health during lockdown. Furthermore, that changes in coping using sex resulting from lockdown would account for further variance in the worsening of health-related behaviors and mental health. Methods: Participants were UK residents, aged 18–60 years, and fluent in English. 789 participants completed an online survey, providing demographic information, self-reported social distancing, loneliness, and coping using sex over a 14-day period during lockdown, and retrospectively preceding lockdown. Outcomes: Participants reported perceived changes in health-related behaviors and mental health symptomatology during lockdown compared to before the pandemic. They also self-reported levels of stress, anxiety and depression during lockdown. Results: Greater coping using sex prior to lockdown predicted positive change in health-related behaviors, for example, higher scores were associated with participants reporting having exercised and slept more. It was also associated with higher trait levels of anxiety, stress and depression during lockdown. Changes in coping using sex from before to during lockdown did not predict perceived changes in health related behaviors or mental health symptomatology. Conclusions: Overall, greater coping using sex prior to lockdown was associated with worse mental health symptomatology during lockdown (anxiety, depression and stress), however, it was also associated with perceived positive change in health-related behaviors compared with before lockdown. This suggests that coping using sex may be associated with negative emotional reactions during lockdown, but may also be linked with positive change in health-promoting behaviors

Phylogenetic Relationships among Deep-Sea and Chemosynthetic Sea Anemones: Actinoscyphiidae and Actinostolidae (Actiniaria: Mesomyaria)

Sea anemones (Cnidaria, Actiniaria) are present in all marine ecosystems, including chemosynthetic environments. The high level of endemicity of sea anemones in chemosynthetic environments and the taxonomic confusion in many of the groups to which these animals belong makes their systematic relationships obscure. We use five molecular markers to explore the phylogenetic relationships of the superfamily Mesomyaria, which includes most of the species that live in chemosynthetic, deep-sea, and polar sea habitats and to test the monophyly of the recently defined clades Actinostolina and Chemosynthina. We found that sea anemones of chemosynthetic environments derive from at least two different lineages: one lineage including acontiate deep-sea taxa and the other primarily encompassing shallow-water taxa

Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders

Background: Inherited platelet function disorders (PFDs) are heterogeneous, and identification of the underlying genetic defects is difficult when based solely on phenotypic and clinical features of the patient. Objective: To analyze 329 genes regulating platelet function, number, and size in order to identify candidate gene defects in patients with PFDs. Patients/methods: Targeted analysis of candidate PFD genes was undertaken after next-generation sequencing of exomic DNA from 18 unrelated index cases with PFDs who were recruited into the UK Genotyping and Phenotyping of Platelets (GAPP) study and diagnosed with platelet abnormalities affecting either Gi signaling (n = 12) or secretion (n = 6). The potential pathogenicity of candidate gene defects was assessed using computational predictive algorithms. Results: Analysis of the 329 candidate PFD genes identified 63 candidate defects, affecting 40 genes, among index cases with Gi signaling abnormalities, while 53 defects, within 49 genes, were identified among patients with secretion abnormalities. Homozygous gene defects were more commonly associated with secretion abnormalities. Functional annotation analysis identified distinct gene clusters in the two patient subgroups. Thirteen genes with significant annotation enrichment for 'intracellular signaling' harbored 16 of the candidate gene defects identified in nine index cases with Gi signaling abnormalities. Four gene clusters, representing 14 genes, with significantly associated gene ontology annotations were identified among the cases with secretion abnormalities, the most significant association being with 'establishment of protein localization.' Conclusion: Our findings demonstrate the genetic complexity of PFDs and highlight plausible candidate genes for targeted analysis in patients with platelet secretion and Gi signaling abnormalities

White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents

Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume in the same individual. We used DT-MRI and structural MRI (sMRI) with voxel based morphometry (VBM) to compare, respectively, the fractional anisotropy (FA) and WM volume of 11 children and adolescents with 22q11DS and 12 controls. Also, within 22q11DS we related differences in WM to severity of schizotypy, and polymorphism of the catechol-O-methyltransferase (COMT) gene. People with 22q11DS had significantly lower FA in inter-hemispheric and brainstem and frontal, parietal and temporal lobe regions after covarying for IQ. Significant WM volumetric increases were found in the internal capsule, anterior brainstem and frontal and occipital lobes. There was a significant negative correlation between increased schizotypy scores and reduced WM FA in the right posterior limb of internal capsule and the right body and left splenium of corpus callosum. Finally, the Val allele of COMT was associated with a significant reduction in both FA and volume of WM in the frontal lobes, cingulum and corpus callosum. Young people with 22q11DS have significant differences in both WM microstructure and volume. Also, there is preliminary evidence that within 22q11DS, some regional differences in FA are associated with allelic variation in COMT and may perhaps also be associated with schizotypy

Time-Resolved Studies of Stick-Slip Friction in Sheared Granular Layers

Sensitive and fast force measurements are performed on sheared granular layers undergoing stick-slip motion, along with simultaneous imaging. A full study has been done for spherical particles with a +-20% size distribution. Stick-slip motion due to repetitive fluidization of the layer occurs for low driving velocities. Between major slip events, slight creep occurs that is variable from one event to the next. The effects of changing the stiffness k and velocity V of the driving system are studied in detail. The stick-slip motion is almost periodic for spherical particles over a wide range of parameters, but becomes irregular when k is large and V is relatively small. At larger V, the motion becomes smoother and is affected by the inertia of the upper plate bounding the layer. Measurements of the period T and amplitude A of the relative motion are presented as a function of V. At a critical value Vc, a transition to continuous sliding motion occurs that is discontinuous for k not too large. The time dependence of the instantaneous velocity of the upper plate and the frictional force produced by the granular layer are determined within individual slipping events. The force is a multi-valued function of the instantaneous velocity, with pronounced hysteresis and a sudden drop prior to resticking. Measurements of vertical displacement reveal a small dilation of the material (about one tenth of the mean particle size in a layer 20 particles deep) associated with each slip event. Finally, optical imaging reveals that localized microscopic rearrangements precede (and follow) each slip event. The behavior of smooth particles is contrasted with that of rough particles.Comment: 20, pages, 17 figures, to appear in Phys. Rev.

Ethical and methodological issues in engaging young people living in poverty with participatory research methods

This paper discusses the methodological and ethical issues arising from a project that focused on conducting a qualitative study using participatory techniques with children and young people living in disadvantage. The main aim of the study was to explore the impact of poverty on children and young people's access to public and private services. The paper is based on the author's perspective of the first stage of the fieldwork from the project. It discusses the ethical implications of involving children and young people in the research process, in particular issues relating to access and recruitment, the role of young people's advisory groups, use of visual data and collection of data in young people's homes. The paper also identifies some strategies for addressing the difficulties encountered in relation to each of these aspects and it considers the benefits of adopting participatory methods when conducting research with children and young people