D Burden

Identification of ZNF313 / RNF114 as a novel psoriasis susceptibility gene

Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage studies have clearly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), but have generated conflicting results for other genomic regions. To overcome this difficulty, we have carried out a genome-wide association scan, where we analyzed more than 408,000 SNPs in an initial sample of 318 cases and 288 controls. Outside of the MHC, we observed a single cluster of disease-associated markers, spanning 47 kb on chromosome 20q13. The analysis of two replication data sets confirmed this association, with SNP rs495337 yielding a combined P-value of 1.4 x 10(-8) in an overall sample of 2679 cases and 2215 controls. Rs495337 maps to the SPATA2 transcript and is in absolute linkage disequilibrium with five SNPs lying in the adjacent ZNF313 gene (also known as RNF114). Real-time PCR experiments showed that, unlike SPATA2, ZNF313 is abundantly expressed in skin, T-lymphocytes and dendritic cells. Furthermore, an analysis of the expression data available from the Genevar database indicated that rs495337 is associated with increased ZNF313 transcripts levels (P = 0.003), suggesting that the disease susceptibility allele may be a ZNF313 regulatory variant tagged by rs495337. Homology searches indicated that ZNF313 is a paralogue of TRAC-1, an ubiquitin ligase regulating T-cell activation. We performed cell-free assays and confirmed that like TRAC-1, ZNF313 binds ubiquitin via an ubiquitin-interaction motif (UIM). These findings collectively identify a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses.

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Psoriasis in Children

Psoriasis often presents in childhood. The diagnosis may be challenging if the disease is mild or the presentation is atypical. All of the forms recognised in adults are encountered in childhood (plaque, guttate, erythrodermic and pustular). Guttate and flexural forms are particularly common in children.Successful management requires education of the child and parents regarding the course of the disease and treatment options. Environmental triggers should be sought out and eliminated where possible. Most patients respond to topical treatment with emollients, coal tar, anthralin (dithranol) or calcipotriol. Treatment is tailored according to patient age, extent and distibution of psoriasis. For those who fail to respond, daycare or inpatient care is appropriate. Phototherapy with UVB may be combined with topical agents. Systemic therapy is required in a minority, usually those with resistant or erythrodermic disease, pustular psoriasis and arthropathic psoriasis. Retinoids are probably the systemic agent of choice. There are few data regarding the use of methotrexate or cyclosporin in childhood psoriais.

Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility

Psoriasis (MIM *177900) is a hyperproliferative skin disorder, characterised by inflammatory cell dermal infiltration, disruption of keratinocyte terminal differentiation, and premature desquamation of the stratum corneum.1 Although the disease pathogenesis is poorly understood, it is well recognised that genetic factors underlie psoriasis susceptibility, as documented by family clustering of the disease and increased concordance rates in monozygotic twin pairs.2,3 To date, genome wide scans have identified seven distinct psoriasis susceptibility regions ( PSORS 1-7 4) and have provided compelling evidence for a major role of the PSORS1 locus on chromosome 6p21.5–9 Linkage disequilibrium (LD) based studies of microsatellite maps have refined the PSORS1 boundaries to a 150 kb interval10–12 harbouring three sets of coding polymorphisms that have repeatedly shown association with psoriasis: HLA-Cw*0602, HCR*269, and CDSN*TTC.13–18 In a recent analysis of a UK family cohort, we have shown that the most common psoriasis susceptibility chromosomes (cluster E) carry HCR*269, CDSN*TTC, and two SNPs (defined as n7 and n9) lying proximal to HLA-C and showing extremely significant disease association. We also observed a rare haplotype (cluster D), marginally over-transmitted to affected patients and likely to have originated from cluster E by a double recombination event, replacing HCR*269 while preserving SNPs 7/9 and CDSN*TTC.19 This observation suggested that CDSN SNPs might be required to confer psoriasis susceptibility, in conjunction with determinants lying in the HLA-C genomic region. CDSN is also a very attractive biological candidate, since corneodesmosin is a desmosomal protein involved in keratinocyte cohesion/desquamation.20–22 With this study, we have sought to validate the hypothesis of CDSN involvement in psoriasis by: (1) confirming that cluster D is a risk haplotype, through the analysis of an independent population, originating from the Gujurat region of northern India; and (2) defining CDSN genetic variation …

Genome-wide association study identifies three novel susceptibility loci for severe Acne vulgaris

Acne vulgaris (acne) is a common inflammatory disorder of the cutaneous pilo-sebaceous unit. Here we perform a genome-wide association analysis in the United Kingdom, comparing severe cases of acne (n=1,893) with controls (n=5,132). In a second stage, we genotype putative-associated loci in a further 2,063 acne cases and 1,970 controls. We identify three genome-wide significant associations: 11q13.1 (rs478304, Pcombined=3.23 × 10(-11), odds ratio (OR) = 1.20), 5q11.2 (rs38055, P(combined) = 4.58 × 10(-9), OR = 1.17) and 1q41 (rs1159268, P(combined) = 4.08 × 10(-8), OR = 1.17). All three loci contain genes linked to the TGFβ cell signalling pathway, namely OVOL1, FST and TGFB2. Transcripts of OVOL1 and TFGB2 have decreased expression in affected compared with normal skin. Collectively, these data support a key role for dysregulation of TGFβ-mediated signalling in susceptibility to acne.

Functional MASP2 single nucleotide polymorphism plays no role in psoriasis.

Background  Psoriasis is a heritable disease and genome‐wide scans have implicated several loci of susceptibility. The gene for MASP‐2, a protease involved in complement activation, is located within one of these loci on chromosome 1p.

Intentional and unintentional medication non-adherence in psoriasis: the role of patients’ medication beliefs and habit strength

Medication non-adherence is a missed opportunity for therapeutic benefit. We assessed “real-world” levels of self-reported non-adherence to conventional and biologic systemic therapies used for psoriasis and evaluated psychological and biomedical factors associated with non-adherence using multivariable analyses. Latent profile analysis was used to investigate whether patients can be categorized into groups with similar medication beliefs. Latent profile analysis categorizes individuals with similar profiles on a set of continuous variables into discrete groups represented by a categorical latent variable. Eight hundred and eleven patients enrolled in the British Association of Dermatologists Biologic Interventions Register were included. Six hundred and seventeen patients were using a self-administered systemic therapy; 22.4% were classified as “non-adherent” (12% intentionally and 10.9% unintentionally). Patients using an oral conventional systemic agent were more likely to be non-adherent compared to those using etanercept or adalimumab (29.2% vs. 16.4%; P ≤ 0.001). Latent profile analysis supported a three-group model; all groups held strong beliefs about their need for systemic therapy but differed in levels of medication concerns. Group 1 (26.4% of the sample) reported the strongest concerns, followed by Group 2 (61%), with Group 3 (12.6%) reporting the weakest concerns. Group 1 membership was associated with intentional non-adherence (odds ratio = 2.27, 95% confidence interval = 1.16−4.47) and weaker medication-taking routine or habit strength was associated with unintentional non-adherence (odds ratio = 0.92, 95% confidence interval = 0.89−0.96). Medication beliefs and habit strength are modifiable targets for strategies to improve adherence in psoriasis.

Risk of serious infections during use of biologic therapies for psoriasis: a systematic review

Background: Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor for liver, pancreatic, and colorectal cancer. T2DM patients show higher incidences of these cancers compared to the non-diabetic (non-DM) population. Current evidence, however, is inconsistent with respect to the incidences of other gastrointestinal (GI) malignancies. Objectives: To determine incidence rates (IRs) of all GI cancers in patients with and without T2DM. Methods: A retrospective cohort study was conducted using the UK Clinical Practice Research Datalink (CPRD) during 1988-2012. A T2DM cohort of antidiabetic drug users was matched to a non-DM reference cohort, by age, sex, and practice. Crude incidence rates (IRs) per 100,000 person-years (105 py) and 95% confidence intervals (CI) were calculated, stratified by age, sex, and calendar period. IRs were compared using the normal theory test. Results: 333,438 T2DM subjects and 333,438 non- DM subjects were analyzed, with a total duration of follow-up of >3.6 million py and 10,977 observed GI cancer cases. Overall, IRs of any GI cancer (IR 330 vs. 276 per 105 py), liver cancer (IR 26 vs. 8.9 per 105 py), pancreatic cancer (IR 65 vs. 31 per 105 py), and colon cancer (IR 119 vs. 109 per 105 py) were significantly higher in the T2DM cohort compared to the non-DM cohort, whereas the IR of esophageal cancer was significantly lower (IR 41 vs. 47 per 105 py, pBackground: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, whi ...The article investigates the special features of state control over international transfer of special-purpose and dual-use goods. It was established what international organizations was created in the international community to determine the principles of control over international transfer of special-purpose and dual-use goods, as well as the question of Ukraines joining the circle of member-states of such organizations. The structure of the system of export control bodies in Ukraine was defined, as well as the main powers of the State Service of Export Control of Ukraine in the sphere of control over international transfer of goods. The essence and the concept of goods over which international transfer state export control is carried out in accordance with the Ukrainian legislation were revealed, as well as special aspects of the procedure of state control over their international transfer.Background: Different antiplatelet regimens are used for secondary prevention after ischemic stroke (IS)/transient ischemic attack (TIA), but studies on the relative effectiveness and safety of each regimen in daily practice are lacking. Objectives: To assess the relative effectiveness and safety of several antiplatelet regimens as secondary prevention in patients after an IS/TIA in clinical practice. Methods: A cohort study was conducted using the Clinical Practice Research Datalink. Patients aged ≥ 18 years with a first diagnosis of IS/TIA in 1998- 2013 were identified. Antiplatelet exposure was categorized into aspirin-dipyridamole, aspirin-only, clopidogrel-only, aspirin-clopidogrel, other regimens, and no-antiplatelet exposure. The primary effectiveness outcome was a composite endpoint of nonfatal IS, nonfatal myocardial infarction (MI), or cardiovascular (CV) death; and the safety outcome was major bleeding. Time-dependent Cox regression analysis was used to assess the association between antiplatelet regimens and CV effectiveness and major bleeding outcomes. Results: We followed 20,552 IS/TIA patients for a median duration of 2.3 years. There were 5,714 composite events during follow-up. All regimens were effective in reducing the primary effectiveness outcome compared to no-antiplatelet exposure. Aspirin-only, clopidogrel-only, aspirin-clopidogrel and other regimens were significantly (p <0.05) less effective compared to aspirin-dipyridamole (HR: 1.35, 1.12, 1.40, and 1.27, respectively), adjusted for age, sex, lifestyle factors, disease history and CV comedications. All other regimens were also significantly (p <0.05) associated with a higher relative risk of major bleeding compared to aspirin-dipyridamole (HR: 1.21, 1.32, 1.78, and 1.37, respectively), adjusted for age, sex, alcohol use, liver and renal disease, major bleeding history and comedications. Conclusions: Compared to aspirin-dipyridamole, all other antiplatelet regimens are less effective in reducing the risk of nonfatal IS, nonfatal MI or CV death, and associated with a higher risk of major bleeding in patients with IS/TIA.Characteristics of Patients at Initiation of Treatment for Primary Chronic Immune ThrombocytopeniaBackground: Guidelines for cardiovascular secondary prevention are based on evidence from relatively old clinical trials and need to be evaluated in daily clinical practice. Objectives: To evaluate effectiveness of the recommended drug classes after an acute coronary syndrome (ACS) for secondary prevention of cardiovascular diseases and all-cause mortality. Methods: This cohort study used data from a representative sample of the French national healthcare insurance system database (EGB). Patients hospitalised for an incident ACS between 2006 and 2011, and aged ≥ 20 years at time of ACS were included in the study. Patients non-exposed to any of the four recommended drug classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting-enzyme inhibitors, ACEI, or angiotensin II receptor blockers, ARB) in the first 3 months following ACS or who died during this period were not included in the cohort. Exposure status was determined daily during follow-up. Effectiveness of the four therapeutic classes in preventing the composite outcome ACS, transient ischemic attack, ischemic stroke, or all-cause-death was estimated using a time-dependent Cox proportional hazards model, which was adjusted for time-fixed confounders measured at baseline (general characteristics and characteristics of the initial ACS) and time-dependent confounders during follow-up (co-morbidities and co-medications). Results: Of the 2874 patients included in the study, 33.9% were women and the median age was 67 years (interquartile range, IQR: 56-77). The median time of follow-up was 3.6 years (IQR: 2.2-5.3). The risk of the composite outcome decreased with use of antiplatelet agents (adjusted hazard ratio (aHR) 0.76, 95% confidence interval (CI) 0.63; 0.91), use of statins (aHR 0.71, 95%CI 0.57; 0.87), and use of ACEI/ARB (aHR 0.67, 95%CI 0.57; 0.80). Use of beta-blockers was not associated with a lower risk of the composite outcome (aHR, 0.90, 95%CI 0.74; 1.09]). Conclusions: Use of antiplatelet agents, statins, and ACEI/ARB after an ACS, but not beta-blockers, was associated with a lower risk of cardiovascular morbidity and all-cause mortality.Abstracts of the 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management, The Convention Centre Dublin, Dublin, Ireland August 25–28, 2016Background: Cough and angioedema are adverse events associated with especially angiotensinconverting enzyme (ACE) inhibitors but also reported with angiotensin receptor blockers (ARBs) and aliskiren, a direct renin inhibitor (DRI). Susceptibility of developing cough/angioedema with ACE inhibitors depends on ethnicity, which is not documented in spontaneous reporting systems of drug safety. Objectives: To assess the impact of ethnicity on the occurrence of cough/angioedema with renin angiotensin system (RAS) inhibitors using information reported to the the World Health Organization database (VigiBase). Methods: A case/non-case study was performed in VigiBase. Cases were defined as reports of cough/angioedema and non-cases were all reports of other adverse events. The reporting countries were divided into three categories: black African countries, East Asian countries and other countries. Logistic regression analysis was used to assess the association between reporting of cough/angioedema with each class of RAS inhibitors stratified by country group and to control for confounding. Results: The reporting of cough with ACE inhibitors was significantly higher in East Asian countries than black African countries and other countries (adjusted reporting odds ratios (RORs): 256, 95%CI (236-278), 48.9, 95%CI (42.7-56.1) and 35.4, 95%CI (34.8- 35.9), respectively. The reporting of angioedema with ACE inhibitors was significantly higher in black African countries than East Asian countries and other countries (adjusted RORs: 55.3, 95%CI (45.5-67.2), 5.29, 95%CI(3.89-7.21) and 16.5, 95%CI (16.1- 16.8), respectively. There was no difference in reporting of cough/angioedema with ARBs and DRI between black African countries, East Asian countries and other countries. Conclusions: Our results by grouping countries according to ethnicity in VigiBase are consistent with previous results in the literature suggesting that the occurrence of cough with ACE inhibitors is higher in East Asian patients and the occurrence of angioedema with ACE inhibitors is higher in black patients. These findings indicate that ethnicity should be included as scientific parameter in pharmacovigilance.An Automatized Model for Sequential Monitoring of Effectiveness of New Drugs using Dronedarone as ExampleGeneral Pharmacological Treatments Preceding A Primary Chronic Immune Thrombocytopenia DiagnosisBackground: Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. There is limited information available about the association of type 1 diabetes (T1D) and psychiatric disorders in children and adolescents. Objectives: To assess the extent of psychiatric medication use before and after the onset of T1D in children and adolescents compared with a reference cohort without T1D. Methods: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System. All children and adolescents <19 years) with at least two insulin dispensings between 1999 and 2009 were identified as a T1D cohort (N=925) and matched with an up to four times larger diabetes-free reference cohort (N=3591) by age and sex. The period prevalences of psychiatric medication use (psycholeptics (ATC N05) and psychoanaleptics (ATC N06)) were calculated by dividing the number of patients with at least one dispensing by the number of patients available in the cohort during that time. Prevalences were calculated from 5 years before until 5 years after the onset of T1D (the index date in both cohorts) and stratified by age, sex, medication subgroup, and before/after the onset of T1D. Results: The mean age of the study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2 vs. 4.7%, respectively, p=0.002). The same pattern was observed for the period after developing T1D (10.4 vs. 7.9% in the T1D and reference cohort respectively, p=0.015). In both cohorts adolescents (15-19 years) and boys had higher prevalences of psychiatric medication use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (mainly anxiolytics). Conclusions: Children with T1D were more likely to use psychiatric medication in the years before and after the onset of type 1 diabetes. This increased use was mainly driven by psycholeptics both before and after onset of T1D.

Differential persistence of four biologic therapies for the treatment of moderate-to-severe psoriasis: a prospective observational cohort study from the British Association of Dermatologists Biologic Interventions Register

RF01 Identifying translational dermatology research priorities in the U.K.: results of an e-Delphi exercise K. Shams, S.J. Brown, S. Langan, S. Nicholls, N. Reynolds and E. Healy Chemokine Research Group, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K., Dermatology & Genetic Medicine, Medical Research Institute, Ninewells Hospital, Dundee, U.K., Medical School, University of Dundee, Dundee, U.K., Faculty of Epidemiology and Population Health, London School of Tropical Medicine, London, U.K., Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada, Dermatology, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle, U.K., Dermatopharmacology, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, U.K. and Southampton Dermatology Centre, Royal South Hants Hospital, University Hospitals Southampton NHS Foundation Trust, Southampton, U.K. There are at least 2000 recognized dermatological conditions, many of which are common and severely impact on quality of life. Significant advances are being made in laboratory-based dermatology research, and there is a need to ensure that such progress directly benefits patients. Translational medicine aims to address this need through improving interactions between laboratory science and clinical practice, to ensure that advances in the former lead to improvements in patient care. However, for most effective utilization of limited resources, there is a need to prioritize and coordinate translational work in dermatology. This study used the well-established consensus-building Delphi technique to help identify the most relevant research questions in translational dermatology research in the U.K. Thirty-two key stakeholders from across the U.K. (including representatives from clinical and academic dermatology, patient support groups and primary care) were invited to form an expert panel. During phase 1 of the electronic Delphi (e-Delphi) exercise, each expert panel member was asked to submit up to 15 research questions deemed most relevant to translational dermatology, across any of the following categories: (i) inflammatory skin disease, (ii) structural skin disorders/genodermatoses, (iii) skin cancer and (iv) miscellaneous. Following removal of duplicate questions, the 228 remaining questions were sent to all 32 panel members during phase 2 for scoring (from 5, most important to 1, least important). During phase 3, the 122 questions with a mean score ≥ 3 were returned to all 27 responders, for the opportunity of rescoring in light of the mean/median scores provided for each question. Questions scored ≥ 3 by > 70% of the responders following phase 3 were regarded as priority translational dermatology research questions (PRQs). The e-Delhi exercise identified 105 PRQs: 40 questions on inflammatory skin disease, 20 on structural skin disorders/genodermatoses, 37 on skin cancer and eight miscellaneous. Questions were wideranging in nature, with an emphasis on psoriasis and eczema in the inflammatory disease category. Many questions in the structural skin disorders/genodermatoses category related to identification of the genetic basis of both common and rare skin disorders. In the skin cancer component, squamous cell carcinoma and melanoma-related questions featured most frequently. Across all categories, developing treatments and elucidating disease mechanisms were recurrent themes. These results provide valuable insight into the current translational research priorities in dermatology in the U.K. We anticipate that our data will impact on translational research strategies in dermatology and will ultimately direct research to maximize opportunities to improve clinical care.

A True Positive Nasal Nodule

A 36-year-old previously healthy immigrant from the Punjab area of Pakistan presented to his family physician when he became aware of lymph node enlargement in his neck. He had no other symptoms, and physical examination confirmed cervical lymphadenopathy but was otherwise unremarkable, as was peripheral blood testing. Nevertheless, given the prevalence of tuberculosis in the patient’s country of origin and a history of previous infective involvement of a family member, the patient was referred to the respiratory department of our hospital for further assessment and evaluation. A computed tomography scan was performed, which demonstrated extensive confluent adenopathy extending from the neck down through the mediastinum into the epigastrium. Lymph node biopsy revealed diffuse replacement by noncaseating granulomas in which 2 acidand alcoholfast bacilli were identified on Ziehl-Neelsen staining, strongly suggesting a diagnosis of tuberculosis. Culture for Mycobacterial species was negative, but the case was thought to represent culture-negative tuberculosis on the basis of the positive histopathologic results, clinical findings, and risk group with family history of disease involvement. Verification by polymerase chain reaction testing was therefore not deemed essential. Anti-tuberculosis treatment was initiated, and the patient was closely followed. Repeat computed tomography was performed 9 months later and showed no improvement in the previously noted lymphadenopathy. Differential diagnoses were sought. A gradually enlarging telangiectatic, fleshy, nodular skin lesion on the tip of the patient’s nose (Figure 1A) had been identified in the meantime by our colleagues in the respiratory department, and referral to our department was made for dermatologic assessment. On clinical evaluation, the skin lesion was thought to represent nodular sarcoidosis. Indeed, histopathologic examination confirmed the presence of noncaseating granulo-