Sleep disordered breathing and subclinical impairment of respiratory function are common in sporadic inclusion body myositis

Relatively little is known about frequency and extent of respiratory problems in sporadic inclusion body myositis (IBM). To address this issue a study of peripheral muscle and respiratory function and related symptoms was performed in a cohort with biopsy-proven IBM. Dyspnoea, daytime sleepiness, dysphagia, spirometry, respiratory muscle strength, arterial blood gas tensions and ventilation during sleep were assessed. Sixteen patients were studied (10 males; age 68.1 ± 9.9 years; disease duration 11.9 ± 5.0 years; body mass index 28.5 ± 4.0 kg/m2). Four reported excessive daytime sleepiness; 8 had at least mild dysphagia; forced vital capacity was <80% predicted normal in 7; sniff nasal inspiratory pressure was reduced in 3; daytime hypoxemia was present in 9 and hypercapnia in one. Sleep study was performed in 15 and revealed sleep disordered breathing (apnoea–hypopnoea index 23.4 ± 12.8 (range 7–50.3) events/h) in all. There were no consistent relationships between respiratory function impairment, occurrence of sleep disordered breathing, and severity of peripheral muscle weakness. Thus, asymptomatic impairment of respiratory function was common and sleep disordered breathing observed in all patients tested, irrespective of daytime respiratory function. This suggests respiratory function testing, including sleep study, should be performed routinely in IBM, irrespective of peripheral muscle function or other disease severity parameters

CRISPR screens identify gene targets at breast cancer risk loci

Background: Genome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in noncoding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association, and identifying the phenotype it mediates, is a major challenge in the interpretation and translation of GWAS. Results: Here, we show that pooled CRISPR screens are highly effective at identifying GWAS target genes and defining the cancer phenotypes they mediate. Following CRISPR mediated gene activation or suppression, we measure proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We perform 60 CRISPR screens and identify 20 genes predicted with high confidence to be GWAS targets that promote cancer by driving proliferation or modulating the DNA damage response in breast cells. We validate the regulation of a subset of these genes by breast cancer risk variants. Conclusions: We demonstrate that phenotypic CRISPR screens can accurately pinpoint the gene target of a risk locus. In addition to defining gene targets of risk loci associated with increased breast cancer risk, we provide a platform for identifying gene targets and phenotypes mediated by risk variants.Natasha K. Tuano, Jonathan Beesley, Murray Manning, Wei Shi, Laura Perlaza, Jimenez, Luis F. Malaver, Ortega, Jacob M. Paynter, Debra Black, Andrew Civitarese, Karen McCue, Aaron Hatzipantelis, Kristine Hillman, Susanne Kaufmann, Haran Sivakumaran, Jose M. Polo, Roger R. Reddel, Vimla Band, Juliet D. French, Stacey L. Edwards, David R. Powell, Georgia Chenevix, Trench, and Joseph Rosenblu

Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

Background: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing. Methods: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation &lt; 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap. Results: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10−8) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways. Conclusions: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response

Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10 &lt;sup&gt;-8&lt;/sup&gt; ) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

The effect of interstate travel on sleep patterns of elite australian rules footballers

Effets du voyage et du décalage horaire sur la quantité et la qualité du sommei

G.P.65: Obstructive sleep apnoea and subclinical impairment of respiratory function are common in sporadic inclusion body myositis

To examine the occurrence of respiratory dysfunction in sporadic inclusion body myositis (IBM) and its relationship to peripheral muscle strength and ventilation during sleep. Anthropometric, muscle strength, dyspnoea, daytime sleepiness and dysphagia data were collected. Spirometry, respiratory muscle strength and arterial blood gas tensions were measured. Ventilation during sleep was assessed by dual channel (oximetry, nasal pressure) home monitoring. Sixteen patients with biopsy-proven IBM were studied (10 males, 6 females; age 68.1 ± 9.9 years; disease duration 11.9 ± 5.0 years; body mass index 28.5 ± 4.0 kg/m2). Four patients reported excessive daytime sleepiness (Epworth Sleepiness Scale ⩾10); 8 had at least mild dysphagia (Dysphagia Outcome Severity Scale ⩽5); forced vital capacity was 45 mmHg) in one. Sleep study was performed in 15 patients and revealed sleep hypoxemia (⩾2% of total sleep time at or below a saturation <90% (TST ⩽ 90)) in 10 and obstructive sleep apnoea (respiratory disturbance index 23.4 ± 12.8 (range 7–50.3) events/h) in all 15. Daytime PaO2 was related to TST ⩽ 90 (r = −0.55, p = 0.04). Asymptomatic impairment of wakeful respiratory function was common and obstructive sleep apnoea was observed in all patients tested, irrespective of daytime respiratory function. This high occurrence probably reflects the combined effects of pharyngeal muscle weakness and sleep-related reduction in muscle activation and ventilatory drive. These findings suggest that tests of respiratory function, including an overnight sleep study, should be performed routinely in IBM patients, irrespective of peripheral muscle function or other non-respiratory disease severity parameters

Quantitative upper airway imaging with anatomic optical coherence tomography

Background: Measurements of upper airway size and shape are important in investigating the pathophysiology of obstructive sleep apnea (OSA) and in devising, applying, and determining the effectiveness of treatment modalities. We describe an endoscopic optical technique (anatomic optical coherence tomography, aOCT) that provides quantitative real-time imaging of the internal anatomy of the human upper airway. Methods: Validation studies were performed by comparing aOCT- and computed tomography (CT)-derived measurements of cross-sectional area (CSA) in (1) conduits in a wax phantom and (2) the velo-, oro-, and hypopharynx during wakefulness in five volunteers. aOCT scanning was performed during sleep in one subject with OSA. Results: aOCT generated images of pharyngeal shape and measurements of CSA and internal dimensions that were comparable to radiographic CT images. The mean difference between aOCT- and CT-derived measurements of CSA in (1) the wax phantom was 2.1 mm2 with limits of agreement (2 SD) from -13.2 to 17.4 mm2 and intraclass correlation coefficient of 0.99 (p < 0.001) and (2) the pharyngeal airway was 14.1 mm2 with limits of agreement from -43.7 to 57.8 mm 2 and intraclass correlation coefficient of 0.89 (p < 0.001). aOCT generated quantitative images of changes in upper airway size and shape before, during, and after an apneic event in an individual with OSA. Conclusions: aOCT generates quantitative, real-time measurements of upper airway size and shape with minimal invasiveness, allowing study over lengthy periods during both sleep and wakefulness. These features should make it useful for study of upper airway behavior to investigate OSA pathophysiology and aid clinical management