A Functional Variant in MicroRNA-146a Promoter Modulates Its Expression and Confers Disease Risk for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a strong genetic predisposition, characterized by an upregulated type I interferon pathway. MicroRNAs are important regulators of immune homeostasis, and aberrant microRNA expression has been demonstrated in patients with autoimmune diseases. We recently identified miR-146a as a negative regulator of the interferon pathway and linked the abnormal activation of this pathway to the underexpression of miR-146a in SLE patients. To explore why the expression of miR-146a is reduced in SLE patients, we conducted short parallel sequencing of potentially regulatory regions of miR-146a and identified a novel genetic variant (rs57095329) in the promoter region exhibiting evidence for association with SLE that was replicated independently in 7,182 Asians (Pmeta = 2.74×10−8, odds ratio = 1.29 [1.18–1.40]). The risk-associated G allele was linked to reduced expression of miR-146a in the peripheral blood leukocytes of the controls. Combined functional assays showed that the risk-associated G allele reduced the protein-binding affinity and activity of the promoter compared with those of the promoter containing the protective A allele. Transcription factor Ets-1, encoded by the lupus-susceptibility gene ETS1, identified in recent genome-wide association studies, binds near this variant. The manipulation of Ets-1 levels strongly affected miR-146a promoter activity in vitro; and the knockdown of Ets-1, mimicking its reduced expression in SLE, directly impaired the induction of miR-146a. We also observed additive effects of the risk alleles of miR-146a and ETS1. Our data identified and confirmed an association between a functional promoter variant of miR-146a and SLE. This risk allele had decreased binding to transcription factor Ets-1, contributing to reduced levels of miR-146a in SLE patients

Transancestral mapping and genetic load in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (B50% of these regions have multiple independent associations); these include 24 novel SLE regions (Po5 10 8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SL

Fundamental Science Investigations to Develop a 6-MV Laser Triggered Gas Switch for ZR: First Annual Report.

In October 2005, an intensive three-year Laser Triggered Gas Switch (LTGS) development program was initiated to investigate and solve observed performance and reliability issues with the LTGS for ZR. The approach taken has been one of mission-focused research: to revisit and reassess the design, to establish a fundamental understanding of LTGS operation and failure modes, and to test evolving operational hypotheses. This effort is aimed toward deploying an initial switch for ZR in 2007, on supporting rolling upgrades to ZR as the technology can be developed, and to prepare with scientific understanding for the even higher voltage switches anticipated needed for future high-yield accelerators. The ZR LTGS was identified as a potential area of concern quite early, but since initial assessments performed on a simplified Switch Test Bed (STB) at 5 MV showed 300-shot lifetimes on multiple switch builds, this component was judged acceptable. When the Z{sub 20} engineering module was brought online in October 2003 frequent flashovers of the plastic switch envelope were observed at the increased stresses required to compensate for the programmatically increased ZR load inductance. As of October 2006, there have been 1423 Z{sub 20} shots assessing a variety of LTGS designs. Numerous incremental and fundamental switch design modifications have been investigated. As we continue to investigate the LTGS, the basic science of plastic surface tracking, laser triggering, cascade breakdown, and optics degradation remain high-priority mission-focused research topics. Significant progress has been made and, while the switch does not yet achieve design requirements, we are on the path to develop successively better switches for rolling upgrade improvements to ZR. This report summarizes the work performed in FY 2006 by the large team. A high-level summary is followed by detailed individual topical reports

Dynamic model of nonmedical opioid use trajectories and potential policy interventions

<div><p></p><p><i>Background</i>: Nonmedical use of pharmaceutical opioid analgesics (POA) increased dramatically over the past two decades and remains a major health problem in the United States, contributing to over 16 000 accidental poisoning deaths in 2010. <i>Objectives</i>: To create a systems-oriented theory/model to explain the historical behaviors of interest, including the various populations of nonmedical opioid users and accidental overdose mortality within those populations. To use the model to explore policy interventions including tamper-resistant drug formulations and strategies for reducing diversion of opioid medicines. <i>Methods</i>: A system dynamics model was constructed to represent the population of people who initiate nonmedical POA usage. The model incorporates use trajectories including development of use disorders, transitions from reliance on informal sharing to paying for drugs, transition from oral administration to tampering to facilitate non-oral routes of administration, and transition to heroin use by some users, as well as movement into and out of the population through quitting and mortality. Empirical support was drawn from national surveys (NSDUH, TEDS, MTF, and ARCOS) and published studies. <i>Results</i>: The model was able to replicate the patterns seen in the historical data for each user population, and the associated overdose deaths. Policy analysis showed that both tamper-resistant formulations and interventions to reduce informal sharing could significantly reduce nonmedical user populations and overdose deaths in the long term, but the modeled effect sizes require additional empirical support. <i>Conclusion</i>: Creating a theory/model that can explain system behaviors at a systems level scale is feasible and facilitates thorough evaluation of policy interventions.</p></div

Opioid-Prescribing Continuity and Risky Opioid Prescriptions

We aimed to better understand the association between opioid-prescribing continuity, risky prescribing patterns, and overdose risk. For this retrospective cohort study, we included patients with long-term opioid use, pulling data from Oregon\u27s Prescription Drug Monitoring Program (PDMP), vital records, and hospital discharge registry. A continuity of care index (COCI) score was calculated for each patient, and we defined metrics to describe risky prescribing and overdose. As prescribing continuity increased, likelihood of filling risky opioid prescriptions and overdose hospitalization decreased. Prescribing continuity is an important factor associated with opioid harms and can be calculated using administrative pharmacy data

High-Risk Prescribing and Opioid Overdose: Prospects for Prescription Drug Monitoring Program Based Proactive Alerts

In order to develop a simple, valid model to identify patients at high risk for opioid overdose-related hospitalization and mortality Oregon PDMP, Vital Records, and Hospital Discharge data were linked to estimate two logistic models; A first model that included a broad range of risk factors from the literature and a second simplified model. ROC curves, sensitivity and specificity of the models were analyzed. Variables retained in the final model were age categories over 35, number of prescribers, number of pharmacies, and prescriptions for long acting opioids, benzodiazepines/sedatives, or carisoprodol. The ability of the model to discriminate between patients who did and did not overdose was reasonably good (AUC = .82, Nagelkerke R2 = .11). The positive predictive value of the model was low. Computationally simple models can identify high risk patients based on prescription history alone, but improvement of the predictive value of models may require information from outside the PDMP. Patient or prescription features that predict opioid overdose may differ from those that predict diversion

Deep sequencing reveals a DAP1 regulatory haplotype that potentiates autoimmunity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease characterized by the development of anti-nuclear antibodies. Susceptibility to SLE is multifactorial, with a combination of genetic and environmental risk factors contributing to disease development. Like other polygenic diseases, a significant proportion of estimated SLE heritability is not accounted for by common disease alleles analyzed by SNP array-based GWASs. Death-associated protein 1 (DAP1) was implicated as a candidate gene in a previous familial linkage study of SLE and rheumatoid arthritis, but the association has not been explored further. RESULTS: We perform deep sequencing across the DAP1 genomic segment in 2032 SLE patients, and healthy controls, and discover a low-frequency functional haplotype strongly associated with SLE risk in multiple ethnicities. We find multiple cis-eQTLs embedded in a risk haplotype that progressively downregulates DAP1 transcription in immune cells. Decreased DAP1 transcription results in reduced DAP1 protein in peripheral blood mononuclear cells, monocytes, and lymphoblastoid cell lines, leading to enhanced autophagic flux in immune cells expressing the DAP1 risk haplotype. Patients with DAP1 risk allele exhibit significantly higher autoantibody titers and altered expression of the immune system, autophagy, and apoptosis pathway transcripts, indicating that the DAP1 risk allele mediates enhanced autophagy, leading to the survival of autoreactive lymphocytes and increased autoantibody. CONCLUSIONS: We demonstrate how targeted sequencing captures low-frequency functional risk alleles that are missed by SNP array-based studies. SLE patients with the DAP1 genotype have distinct autoantibody and transcription profiles, supporting the dissection of SLE heterogeneity by genetic analysis