Nucleic Acid-Sensing and Interferon-Inducible Pathways Show Differential Methylation in MZ Twins Discordant for Lupus and Overexpression in Independent Lupus Samples: Implications for Pathogenic Mechanism and Drug Targeting.

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease with genomic and non-genomic contributions to risk. We hypothesize that epigenetic factors are a significant contributor to SLE risk and may be informative for identifying pathogenic mechanisms and therapeutic targets. To test this hypothesis while controlling for genetic background, we performed an epigenome-wide analysis of DNA methylation in genomic DNA from whole blood in three pairs of female monozygotic (MZ) twins of European ancestry, discordant for SLE. Results were replicated on the same array in four cell types from a set of four Danish female MZ twin pairs discordant for SLE. Genes implicated by the epigenetic analyses were then evaluated in 10 independent SLE gene expression datasets from the Gene Expression Omnibus (GEO). There were 59 differentially methylated loci between unaffected and affected MZ twins in whole blood, including 11 novel loci. All but two of these loci were hypomethylated in the SLE twins relative to the unaffected twins. The genes harboring these hypomethylated loci exhibited increased expression in multiple independent datasets of SLE patients. This pattern was largely consistent regardless of disease activity, cell type, or renal tissue type. The genes proximal to CpGs exhibiting differential methylation (DM) in the SLE-discordant MZ twins and exhibiting differential expression (DE) in independent SLE GEO cohorts (DM-DE genes) clustered into two pathways: the nucleic acid-sensing pathway and the type I interferon pathway. The DM-DE genes were also informatically queried for potential gene-drug interactions, yielding a list of 41 drugs including a known SLE therapy. The DM-DE genes delineate two important biologic pathways that are not only reflective of the heterogeneity of SLE but may also correlate with distinct IFN responses that depend on the source, type, and location of nucleic acid molecules and the activated receptors in individual patients. Cell- and tissue-specific analyses will be critical to the understanding of genetic factors dysregulating the nucleic acid-sensing and IFN pathways and whether these factors could be appropriate targets for therapeutic intervention

Laminate polyethylene window development for large aperture millimeter receivers

New experiments that target the B-mode polarization signals in the Cosmic Microwave Background require more sensitivity, more detectors, and thus larger-aperture millimeter-wavelength telescopes, than previous experiments. These larger apertures require ever larger vacuum windows to house cryogenic optics. Scaling up conventional vacuum windows, such as those made of High Density Polyethylene (HDPE), require a corresponding increase in the thickness of the window material to handle the extra force from the atmospheric pressure. Thicker windows cause more transmission loss at ambient temperatures, increasing optical loading and decreasing sensitivity. We have developed the use of woven High Modulus Polyethylene (HMPE), a material 100 times stronger than HDPE, to manufacture stronger, thinner windows using a pressurized hot lamination process. We discuss the development of a specialty autoclave for generating thin laminate vacuum windows and the optical and mechanical characterization of full scale science grade windows, with the goal of developing a new window suitable for BICEP Array cryostats and for future CMB applications

Improving hand hygiene compliance in nursing homes: Protocol for a cluster randomized controlled trial (HANDSOME Study)

Background: Hand hygiene compliance is considered the most (cost-)effective measure for preventing health care-associated infections. While hand hygiene interventions have frequently been implemented and assessed in hospitals, there is limited knowledge about hand hygiene compliance in other health care settings and which interventions and implementation methods are effective. Objective: This study aims to evaluate the effect of a multimodal intervention to increase hand hygiene compliance of nurses in nursing homes through a cluster randomized controlled trial (HANDSOME study). Methods: Nursing homes were randomly allocated to 1 of 3 trial arms: Receiving the intervention at a predetermined date, receiving the identical intervention after an infectious disease outbreak, or serving as a control arm. Hand hygiene was evaluated in nursing homes by direct observation at 4 timepoints. We documented compliance with the World Health Organization's 5 moments of hand hygiene, specifically before touching a patient, before a clean/aseptic procedure, after body fluid exposure risk, after touching a patient, and after touching patient surroundings. The primary outcome is hand hygiene compliance of the nurses to the standards of the World Health Organization. The secondary outcome is infectious disease incidence among residents. Infectious disease incidence was documented by a staff member at each nursing home unit. Outcomes will be compared with the presence of norovirus, rhinovirus, and Escherichia coli on surfaces in the nursing homes, as measured using quantitative polymerase chain reaction. Results: The study was funded in September 2015. Data collection started in October 2016 and was completed in October 2017. Data analysis will be completed in 2020. Conclusions: HANDSOME studies the effectiveness of a hand hygiene intervention specifically for the nursing hom

Trans-Ethnic Mapping of BANK1 Identifies Two Independent SLE-Risk Linkage Groups Enriched for Co-Transcriptional Splicing Marks

BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combinedwith a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomicmarks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways.The work presented in this paper has been supported by the Ministerio de Economía y Competitividad, Spain (SAF2016-78631-P), partly co-financed by FEDER funds of the European Union, the Gustaf den V:e-80-års Fond and the Swedish Association against Rheumatism to M.E.A-R. In addition, this work was financed by the NIH P01 grant P01-AI-083194 to C.D.L., J.B.H., R.K., and M.E.A-R. JBH: NIH grants: R01 AI024717, U01 HG00866, P30 AR070549 and U01 AI130830 and the US Department of Veterans Affairs: I01 BX001834.C.D.L.: Center for Public Health Genomics. R.K.: NIH grant R01-AR33062. J.A.J.: NIH grants U54GM104938, P30AR053483

Seroprevalence of SARS-CoV-2 antibodies among healthcare workers in Dutch hospitals after the 2020 first wave:a multicentre cross-sectional study with prospective follow-up

BACKGROUND: We aimed to estimate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence and describe its determinants and associated symptoms among unvaccinated healthcare workers (HCWs) after the first wave of the pandemic.METHODS: HCWs from 13 Dutch hospitals were screened for antibodies against the spike protein of SARS-CoV-2 in June-July 2020 and after three months. Participants completed a retrospective questionnaire on determinants for occupational and community exposure to SARS-CoV-2 and symptoms suggestive of COVID-19 experienced since January 2020. The seroprevalence was calculated per baseline characteristic and symptom at baseline and after follow-up. Adjusted odds ratios (aOR) for seropositivity were determined using logistic regression.RESULTS: Among 2328 HCWs, 323 (13.9%) were seropositive at enrolment, 49 of whom (15%) reported no previous symptoms suggestive of COVID-19. During follow-up, only 1% of the tested participants seroconverted. Seroprevalence was higher in younger HCWs compared to the mid-age category (aOR 1.53, 95% CI 1.07-2.18). Nurses (aOR 2.21, 95% CI 1.34-3.64) and administrative staff (aOR 1.87, 95% CI 1.02-3.43) had a higher seroprevalence than physicians. The highest seroprevalence was observed in HCWs in the emergency department (ED) (aOR 1.79, 95% CI 1.10-2.91), the lowest in HCWs in the intensive, high, or medium care units (aOR 0.47, 95% CI 0.31-0.71). Chronic respiratory disease, smoking, and having a dog were independently associated with a lower seroprevalence, while HCWs with diabetes mellitus had a higher seroprevalence. In a multivariable model containing all self-reported symptoms since January 2020, altered smell and taste, fever, general malaise/fatigue, and muscle aches were positively associated with developing antibodies, while sore throat and chills were negatively associated.CONCLUSIONS: The SARS-CoV-2 seroprevalence in unvaccinated HCWs of 13 Dutch hospitals was 14% in June-July 2020 and remained stable after three months. A higher seroprevalence was observed in the ED and among nurses, administrative and young staff, and those with diabetes mellitus, while a lower seroprevalence was found in HCWs in intensive, high, or medium care, and those with self-reported lung disease, smokers, and dog owners. A history of altered smell or taste, fever, muscle aches and fatigue were independently associated with the presence of SARS-CoV-2 antibodies in unvaccinated HCWs.</p

Identification of a regulatory pathway governing TRAF1 via an arthritis-associated non-coding variant

TRAF1/C5 was among the first loci shown to confer risk for inflammatory arthritis in the absence of an associated coding variant, but its genetic mechanism remains undefined. Using Immunochip data from 3,939 patients with juvenile idiopathic arthritis (JIA) and 14,412 control individuals, we identified 132 plausible common non-coding variants, reduced serially by single-nucleotide polymorphism sequencing (SNP-seq), electrophoretic mobility shift, and luciferase studies to the single variant rs7034653 in the third intron of TRAF1. Genetically manipulated experimental cells and primary monocytes from genotyped donors establish that the risk G allele reduces binding of Fos-related antigen 2 (FRA2), encoded by FOSL2, resulting in reduced TRAF1 expression and enhanced tumor necrosis factor (TNF) production. Conditioning on this JIA variant eliminated attributable risk for rheumatoid arthritis, implicating a mechanism shared across the arthritis spectrum. These findings reveal that rs7034653, FRA2, and TRAF1 mediate a pathway through which a non-coding functional variant drives risk of inflammatory arthritis in children and adults

Mutation screening of NOS1AP gene in a large sample of psychiatric patients and controls

<p>Abstract</p> <p>Background</p> <p>The gene encoding carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (<it>NOS1AP</it>) is located on chromosome 1q23.3, a candidate region for schizophrenia, autism spectrum disorders (ASD) and obsessive-compulsive disorder (OCD). Previous genetic and functional studies explored the role of <it>NOS1AP </it>in these psychiatric conditions, but only a limited number explored the sequence variability of <it>NOS1AP</it>.</p> <p>Methods</p> <p>We analyzed the coding sequence of <it>NOS1AP </it>in a large population (n = 280), including patients with schizophrenia (n = 72), ASD (n = 81) or OCD (n = 34), and in healthy volunteers controlled for the absence of personal or familial history of psychiatric disorders (n = 93).</p> <p>Results</p> <p>Two non-synonymous variations, V37I and D423N were identified in two families, one with two siblings with OCD and the other with two brothers with ASD. These rare variations apparently segregate with the presence of psychiatric conditions.</p> <p>Conclusions</p> <p>Coding variations of <it>NOS1AP </it>are relatively rare in patients and controls. Nevertheless, we report the first non-synonymous variations within the human <it>NOS1AP </it>gene that warrant further genetic and functional investigations to ascertain their roles in the susceptibility to psychiatric disorders.</p

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 (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 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 SLE