We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near
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, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.
This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
Staining with anti-IgE further confirmed that this increase in FCER1A levels also translates into increased IgE surface expression on monocytes (Fig 2, B). Besides classical monocytes, rs2427837 was ...correlated with FCER1A levels in pDCs. In particular, a study in school-aged children found that FCER1A-positive pDC subsets could differentiate children with asthma from atopic children without asthma.4 In addition, pDCs expressing CD123 (IL3-receptor-alpha) are recruited to the lungs during inflammation and migrate to the draining lymph nodes to augment TH2 responses in a mouse model of allergic airway disease.6 These pDCs exhibit an activated inflammatory phenotype in the nasal mucosa following stimulation with TNF-α: here, they favor a TH2 polarizing profile and can markedly increase in number to trigger airway allergy. ...not surprisingly, they are associated with a higher risk of experiencing asthma attacks and a severe form of the disease. ...the associations that we made between FCER1A gene expression and asthma in the Singapore Systems Immunology cohort and Barn/Children Allergy/Asthma Milieu Stockholm Epidemiologic study cohort derive from whole blood samples, not from individual immune cell subsets. Importantly, we have confirmed the association of the allergy-relevant SNP rs2427837 with FCER1A and believe that targeting FCER1A in monocytes and pDCs might constitute a novel option to reduce allergen-specific responses.Methods Flow cytometry staining and characterization of FCER1A protein levels in immune subsets The relevant details for the discovery and validation cohorts from the Singapore Chinese cohort have been previously described.E1 For the discovery cohort, whole blood samples were lysed with lysis buffer and stained with anti–FcεRI-FITC (AER37, eBioscience, San Diego, Calif), anti–IgE-APC (MB10-5C4, Miltenyi Biotec, Bergisch Gladbach, Germany), and anti–CD123-PerCP-Cy5.5 (6H6, eBioscience) antibodies.
Background
Some children with asthma experience exacerbations despite long‐acting beta2‐agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome‐wide study ...until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium.
Methods
A meta‐analysis of genome‐wide association studies (meta‐GWAS) was performed in 1,425 children and young adults with asthma (age 6‐21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma.
Results
Genome‐wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta‐analysed. Eight independent variants were suggestively (P‐value threshold ≤5 × 10−6) associated with exacerbations despite LABA use.
Conclusion
No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short‐acting beta2‐agonists (SABA). These loci merit further investigation in response to LABA and SABA use.
Background Allergic rhinitis (AR) and asthma are common allergic conditions with a shared genetic component to their cause. The 17q12-21 locus includes several genes that have been linked to asthma ...susceptibility, but the role of this locus in AR is unclear. Asthma and AR in adults of Chinese ethnicity in Singapore are predominately caused by sensitization against house dust mites with a nearly complete penetrance of the allergen, which presents a unique opportunity for accurately identifying genetic associations with allergic diseases. Objective We sought to define the functional role of 17q12-21 in patients with AR and allergic asthma. Methods We asked whether single nucleotide polymorphisms (SNPs) in the 17q12-21 locus were associated with AR or asthma in a cohort of 3460 ethnic Chinese subjects residing in Singapore (1435 in the discovery phase and 2025 in the validation phase). Full-blood mRNA gene expression data, plasma IgE levels, and immune cell frequencies in peripheral blood were tested against the tag SNP genotypes. Luciferase assays were used to measure the effect of putative promoter SNPs on expression of the asthma-associated orosomucoid-like 3 gene (ORMDL3). Results Within 17q12-21, only the tag SNP rs8076131 was significantly associated with asthma ( P = 8.53 × 10−10 ; odds ratio, 0.6715), and AR status was independent of SNPs in this region. C-A alleles at rs8076131 resulted in significantly increased ORMDL3 expression in HEK293 cells in vitro relative to T-G alleles. Moreover, subjects with the risk genotype AA exhibited significantly higher total IgE levels and higher blood eosinophil counts than those with the lower-risk genotypes. Conclusion The 17q12-21 locus has a strong genetic association with allergic asthma but not with AR. The polymorphic effect of this locus is attributed to the linkage set tagged by rs8076131, which affects the expression of ORMDL3 , protein phosphatase 1, regulatory inhibitor subunit 1B ( PPP1R1B ), zona pellucida binding protein 2 ( ZPBP2 ), and gasdermin B (GSDMB) and is correlated with high IgE levels and eosinophil counts in subjects bearing the risk genotype.
Abstract Introduction The purpose of this study was to determine whether there is a difference in the in vivo diagnostic accuracy of digital radiography (DR) and cone-beam computed tomography (CBCT) ...imaging in the detection of vertical root fracture (VRF). The presence/absence of VRF was confirmed by visual inspection of the extracted root surface and was the reference standard against which both imaging modalities were compared. Methods Twenty-one unsalvageable teeth from 20 patients that had been radiographed and scanned with CBCT imaging were included in the study. The teeth were atraumatically extracted and visually inspected under a microscope to confirm the presence/absence of fracture. The widest point of each fracture was recorded using an optical coherence tomography scanner in order to quantify the size of fractures. Images were viewed under standardized conditions by 13 examiners and repeated 2 weeks later to assess their consistency. Results DR and CBCT imaging showed similarly poor sensitivity of 0.16 and 0.27, respectively. Both imaging modalities had similarly high specificity of 0.92 and 0.83, respectively. There was no statistical difference between the diagnostic accuracy of either imaging modality. Fracture width did not affect the detection rate of either imaging modality. Receiver operating characteristic analysis revealed mean Az values of 0.535 and 0.552 for DR and CBCT imaging, respectively. Conclusions Both DR and CBCT imaging have significant limitations when detecting vertical root fractures.
Summary
Several mathematical models have been developed in the past to consider reliability when designing energy systems. However, these models focus on the system reliability which only considers ...the operability of the system. Hence, a reliability indicator called supply reliability is introduced to explicitly assess an energy system's reliability meeting the desired energy demand. Besides, previous models can only allocate equipment with identical sizes and equipment reliability. This could overdesign systems and ignore the possibility of allocating a combination of different equipment sizes and reliability. This paper presents a combinatory matrix methodology for allocating equipment with different sizes and reliabilities to improve supply reliability of an energy system design. This combinatory matrix method is a novel feature that allows decision‐makers to efficiently evaluate various configurations of equipment based on size and reliability. A case study consisting of a power distribution network is first presented and solved as a pedagogical example to illustrate the methodology and features of the proposed approach. Then, a large‐scale power system case study in Malaysia combining existing conventional power equipment and a palm‐based bioelectricity supply chain is solved. Based on the optimized results, the redundancy allocated increased the energy generated from the bioelectricity supply chain by 74.14% and cost by 82.96% to achieve the desired energy demand at high supply reliability. This allows decision‐makers to determine the cost associated with improving supply reliability for an energy system.
A new reliability indicator known as supply reliability is introduced to explicitly assess the reliability of an energy system to supply and meet a desired energy demand.
Matrix combinatory method is utilized to allocate equipment with various sizes and reliabilities.
Integrates easily with other design optimization frameworks to incorporate reliability aspect into design.
...we also estimated the association P values of these SNPs on comparing control subjects with sensitized subjects with and without AR (see Tables E5 and E6 in this article's Online Repository at ...www.jacionline.org). ...we performed the first independent replication of the genome-wide association study (GWAS) meta-analysis for AR and sensitization.
Background Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently ...unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. Objective We sought to identify disease associations and the functional effect of BDNF genetic variants in patients with moderate-to-severe AR. Methods Tagging single nucleotide polymorphisms (SNPs) spanning the BDNF gene were selected from the human HapMap Han Chinese from Beijing (CHB) data set, and associations with moderate-to-severe AR were assessed in 2 independent cohorts of Chinese patients (2216 from Shandong province and 1239 living in Singapore). The functional effects of the BDNF genetic variants were determined by using both in vitro and ex vivo assays. Results The tagging SNP rs10767664 was significantly associated with the risk of moderate-to-severe AR in both Singapore Chinese ( P = .0017; odds ratio, 1.324) and Shandong Chinese populations ( P = .039; odds ratio, 1.180). The coding nonsynonymous SNP rs6265 was in perfect linkage with rs10767664 and conferred increased BDNF protein secretion by a human cell line in vitro . Subjects bearing the AA genotype of rs10767664 exhibited increased risk of moderate-to-severe AR and displayed increased BDNF protein and total IgE levels in plasma. Using a large-scale expression quantitative trait locus study, we demonstrated that BDNF SNPs are significantly associated with altered BDNF concentrations in peripheral blood. Conclusion A common genetic variant of the BDNF gene is associated with increased risk of moderate-to-severe AR, and the AA genotype is associated with increased BDNF mRNA levels in peripheral blood. Together, these data indicate that functional BDNF gene variants increase the risk of moderate-to-severe AR.
This paper presents an integrated mathematical optimisation approach to synthesise a bioelectricity supply chain network with minimal costs. Detailed economic evaluation was performed to determine ...the optimum location of centralised or decentralised biomass pre-treatment and power plants. Once the optimum bioelectricity supply chain network is established, input-output modelling of the network is formed. Next, feasible operating range analysis is performed. A palm-based bioelectricity supply chain case study in Malaysia is used to illustrate the proposed approach. Based on the optimised results, a total of 80.90 MW of bioelectricity are generated with an estimated net present value of USD 123.94 million and a payback period of 5 years. Meanwhile, the feasible operating range analysis indicated that the synthesised bioelectricity supply chain network possessed multiple feasible operating ranges; 5.06–10.04 MW, 11.88–36.08 MW and 44.26–101.16 MW. Based on the result, the decision makers can determine the potential of the future bioelectricity projects according to different seasons of supply and demand variations.
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•Integrated approach for bioelectricity supply chain network is presented.•Optimum location of centralised/decentralised technologies is determined.•Feasible operating range analysis is performed for the synthesised network.•Potential for future bioelectricity projects can be determined.
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