Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, systemic autoimmune disease characterized by autoantibody formation. Previously published genome-wide association studies (GWAS) have investigated SLE as a single phenotype. Therefore, we conducted a GWAS to identify genetic factors associated with anti-dsDNA autoantibody production, a SLE-related autoantibody with diagnostic and clinical importance. Using two independent datasets, over 400,000 single nucleotide polymorphisms (SNPs) were studied in a total of 1,717 SLE cases and 4,813 healthy controls. Anti-dsDNA autoantibody positive (anti-dsDNA +, n = 811) and anti-dsDNA autoantibody negative (anti-dsDNA -, n = 906) SLE cases were compared to healthy controls and to each other to identify SNPs associated specifically with these SLE subtypes. SNPs in the previously identified SLE susceptibility loci STAT4, IRF5, ITGAM, and the major histocompatibility complex were strongly associated with anti-dsDNA + SLE. Far fewer and weaker associations were observed for anti-dsDNA - SLE. For example, rs7574865 in STAT4 had an OR for anti-dsDNA + SLE of 1.77 (95% CI 1.57-1.99, p = 2.0E-20) compared to an OR for anti-dsDNA - SLE of 1.26 (95% CI 1.12-1.41, p = 2.4E-04), with pheterogeneity<0.0005. SNPs in the SLE susceptibility loci BANK1, KIAA1542, and UBE2L3 showed evidence of association with anti-dsDNA + SLE and were not associated with anti-dsDNA - SLE. In conclusion, we identified differential genetic associations with SLE based on anti-dsDNA autoantibody production. Many previously identified SLE susceptibility loci may confer disease risk through their role in autoantibody production and be more accurately described as autoantibody propensity loci. Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE

Assessment of Chronic Illness-Related Cognitive Fusion: Preliminary Development and Validation of a New Scale with an IBD Sample

Although research recognizes the advantages of creating specific content measures, no specific measure of chronic illness-related cognitive fusion had been developed to date. The current study presents the development and validation of the Cognitive Fusion Questionnaire-Chronic Illness (CFQ-CI) in a sample of inflammatory bowel disease (IBD) patients and the analysis of the role of this construct in the psychological health of those patients. Results indicated that the 7-item CFQ-CI was a unidimensional measure of cognitive fusion in patients with chronic illnesses, and that scores had adequate/good internal consistency and construct, convergent, and discriminant validity. This study also showed that chronic illness-related cognitive fusion as assessed by the CFQ-CI acted as a mediator in the association between both IBD-related symptoms and shame with quality of life. The development of the CFQ-CI may thus contribute to a better understanding of the mechanisms influencing functional outcomes in chronic illness

The development and validation of the Addiction-like Eating Behaviour Scale

Background: Overeating and obesity are frequently attributed to an addiction to food. However, there is currently a lack of evidence to support the idea that certain foods contain any specific addictive substance. An alternative approach is to focus on dimensions of observable behaviour, which may underpin a behavioural addiction to eating. To facilitate this, it is necessary to develop a tool to quantify addiction-like eating behaviour, which is not based on the clinical criteria for substance dependence. The current study provides initial validation of the Addiction-like Eating Behaviour Scale (AEBS). Methods: English speaking male and female participants (N=511) from a community sample completed the AEBS, alongside a range of other health- and eating-related questionnaires including the Yale Food Addiction Scale (YFAS) and Binge Eating Scale (BES). Participants also provided their height and weight to enable calculation of body mass index (BMI). Finally, to assess test–retest reliability, an additional 70 participants completed the AEBS twice, 2 weeks apart. Results: Principle components analysis revealed that a two-factor structure best accounted for the data. Factor 1 consisted of items that referred to appetitive drive, whereas factor two consisted of items that referred to dietary control practices. Both subscales demonstrated good internal reliability and test–retest reliability, and a confirmatory factor analysis confirmed the two-factor scale structure. AEBS scores correlated positively with body mass index (BMI) (P<0.001) and other self-report measures of overeating. Importantly, the AEBS significantly predicted variance in BMI above that accounted for by both the YFAS and BES (P=0.027). Conclusions: The AEBS provides a valid and reliable tool to quantify the behavioural features of a potential ‘eating addiction’. In doing so, the AEBS overcomes many limitations associated with applying substance-dependence criteria to eating

Psychometric properties and longitudinal validation of the self-reporting questionnaire (SRQ-20) in a Rwandan community setting: a validation study

Background: This study took place to enable the measurement of the effects on mental health of a psychosocial intervention in Rwanda. It aimed to establish the capacities of the Self-Reporting Questionnaire (SRQ-20) to screen for mental disorder and to assess symptom change over time in a Rwandan community setting. Methods. The SRQ-20 was translated into Kinyarwanda in a process of forward and back-translation. SRQ-20 data were collected in a Rwandan setting on 418 respondents; a random subsample of 230 respondents was assessed a second time with a three month time interval. Internal reliability was tested using Cronbach's alpha. The optimal cut-off point was determined by calculating Receiver Operating Curves, using semi-structured clinical interviews as standard in a random subsample of 99 respondents. Subsequently, predictive value, likelihood ratio, and interrater agreement were calculated. The factor structure of the SRQ-20 was determined through exploratory factor analysis. Factorial invariance over time was tested in a multigroup confirmatory factor analysis. Results: The reliability of the SRQ-20 in women ( = 0.85) and men ( = 0.81) could be considered good. The instrument performed moderately well in detecting common mental disorders, with an area

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development

Prenatal exposures and exposomics of asthma

This review examines the causal investigation of preclinical development of childhood asthma using exposomic tools. We examine the current state of knowledge regarding early-life exposure to non-biogenic indoor air pollution and the developmental modulation of the immune system. We examine how metabolomics technologies could aid not only in the biomarker identification of a particular asthma phenotype, but also the mechanisms underlying the immunopathologic process. Within such a framework, we propose alternate components of exposomic investigation of asthma in which, the exposome represents a reiterative investigative process of targeted biomarker identification, validation through computational systems biology and physical sampling of environmental medi

The LUX-ZEPLIN (LZ) Experiment

We describe the design and assembly of the LUX-ZEPLIN experiment, a direct detection search for cosmic WIMP dark matter particles. The centerpiece of the experiment is a large liquid xenon time projection chamber sensitive to low energy nuclear recoils. Rejection of backgrounds is enhanced by a Xe skin veto detector and by a liquid scintillator Outer Detector loaded with gadolinium for efficient neutron capture and tagging. LZ is located in the Davis Cavern at the 4850' level of the Sanford Underground Research Facility in Lead, South Dakota, USA. We describe the major subsystems of the experiment and its key design features and requirements

FcγRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human.

Several tolerance “checkpoints” exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease. Its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb leads to increased deletion and anergy of autoreactive immature B cells, but despite this autoreactive B cells expand in the germinal center and serum autoantibodies are produced, even in response to exogenous non-self antigen. Thus, we show FcγRIIb has opposing effects on pre- and post-immune tolerance checkpoints, and suggest B cell tolerance requires the control of “bystander” germinal center B cells with low or no affinity for the immunization antigen.This work was funded by the Wellcome Trust (Programme Grant Number 083650/Z/07/Z to KGCS) and supported by the NIHR Cambridge Biomedical Research Centre. ME was funded by the Wellcome Trust (Programme Grant Number 083650/Z/07/Z), by a Junior Team Leader starting grant from the Laboratory of Excellence in Research on Medication and Innovative Therapeutics (LabEx LERMIT) supported by a grant from ANR (ANR-10-LABX-33) under the program “Investissements d'Avenir” (ANR-11-IDEX-0003-01) and by an ANR @RAction starting grant (ANR-14-ACHN- 0008). KGCS is an NIHR Senior Clinical Investigator and a Distinguished Innovator of the Lupus Research Institute

Maternal blood cadmium, lead and arsenic levels, nutrient combinations, and offspring birthweight

Abstract Background Cadmium (Cd), lead (Pb) and arsenic (As) are common environmental contaminants that have been associated with lower birthweight. Although some essential metals may mitigate exposure, data are inconsistent. This study sought to evaluate the relationship between toxic metals, nutrient combinations and birthweight among 275 mother-child pairs. Methods Non-essential metals, Cd, Pb, As, and essential metals, iron (Fe), zinc (Zn), selenium (Se), copper (Cu), calcium (Ca), magnesium (Mg), and manganese (Mn) were measured in maternal whole blood obtained during the first trimester using inductively coupled plasma mass spectrometry. Folate concentrations were measured by microbial assay. Birthweight was obtained from medical records. We used quantile regression to evaluate the association between toxic metals and nutrients due to their underlying wedge-shaped relationship. Ordinary linear regression was used to evaluate associations between birth weight and toxic metals. Results After multivariate adjustment, the negative association between Pb or Cd and a combination of Fe, Se, Ca and folate was robust, persistent and dose-dependent (p < 0.05). However, a combination of Zn, Cu, Mn and Mg was positively associated with Pb and Cd levels. While prenatal blood Cd and Pb were also associated with lower birthweight. Fe, Se, Ca and folate did not modify these associations. Conclusion Small sample size and cross-sectional design notwithstanding, the robust and persistent negative associations between some, but not all, nutrient combinations with these ubiquitous environmental contaminants suggest that only some recommended nutrient combinations may mitigate toxic metal exposure in chronically exposed populations. Larger longitudinal studies are required to confirm these findings