A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 x 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 x 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Comparison of pramipexole and amisulpride on alertness, autonomic and endocrine functions in healthy volunteers

Rationale In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D2/D3 autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger–Westphal nucleus (via a putative meso-pupillomotor pathway).Objectives We investigated the hypothesis that amisulpride, a D2/D3 receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions.Materials and methods Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA.Results Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels.Conclusions The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D2/D3 receptors on VTA neurones and in the tuberoinfundibular system

Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers

Rationale: Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be “switched off” by the ?2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects. Objective: The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers. Methods: Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary “fatigue waves” (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons. Results: Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions. Conclusions: Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation. <br/

Arousal and the pupil: why diazepam-induced sedation is not accompanied by miosis

Rationale There is a close relationship between arousal and pupil diameter, decrease in the level of arousal being accompanied by constriction of the pupil (miosis), probably reflecting the attenuation of sympathetic outflow as sedation sets in. Paradoxically, sedation induced by benzodiazepines is not accompanied by miosis.Objective The objective of this study was to examine the hypothesis that diazepam may attenuate both the sympathetic and the opposing parasympathetic outflow to the iris, which may mask the miosis. Dapiprazole (sympatholytic) and tropicamide (parasympatholytic) were applied topically, together with the cold pressor test (CPT), to manipulate the sympathetic/parasympathetic balance.Materials and methods Sixteen healthy male volunteers participated in four weekly sessions according to a balanced double-blind protocol. Diazepam 10 mg (two sessions) and placebo (two sessions), associated with either 0.01% tropicamide or 0.5% dapiprazole eyedrops, were administered orally. Pupil diameter, light and darkness reflexes and pupillary sleepiness waves were recorded with infrared video pupillometry, alertness was measured by critical flicker fusion frequency (CFFF) and visual analogue scales (VAS), blood pressure and heart rate by conventional methods. CPT was applied after post-treatment testing. Data were analysed by analysis of variance, with multiple comparisons.Results Diazepam caused sedation (reduction in VAS alertness scores and CFFF, increase in sleepiness waves), dapiprazole had a sympatholytic and tropicamide a parasympatholytic effect on the pupil. Diazepam had no effect on pupil diameter and reflexes or their modifications by the antagonists. CPT increased pupil diameter, blood pressure and heart rate, and the increase only in systolic blood pressure was attenuated by diazepam.Conclusions Diazepam-induced sedation is not accompanied by any change in either the sympathetic or parasympathetic influence on the iris