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Phenome-wide association study and functional annotation of hemoglobin A1c-associated variants in African populations
Get PDFBackground: Glycated hemoglobin (HbA1c) measures the average blood sugar level over the past three months. As a vital biomarker of blood glucose levels, it is used to diagnose Type-2 diabetes mellitus (T2D) and monitor glycemic control. A heritability estimate of 47% to 59% suggests that about half of the variation in HbA1c levels can be attributed to genetic factors. Despite African populations being the most genetically diverse and unique for fine-mapping, there is a paucity of data on the genetic drivers of HbA1c in African individuals. In this study, we performed functional annotation and a Phenome-Wide Association Study (PheWAS) of HbA1c-associated variants in two African populations.
Method: In this study, we utilized summary statistics of the HbA1c GWAS meta-analysis of 7,526 individuals from South Africa and Uganda to conduct a PheWAS using GWASATLAS. We also performed a functional analysis using the functional mapping and annotation (FUMA) tool. Single nucleotide polymorphisms (SNPs) were prioritized using the SNP2GENE function, while the gene expression patterns and shared molecular functions were explored in the GENE2FUNC.
Result: Three genome-wide significant loci were identified with the lead SNPs: rs6724428, rs148228241, and rs8045544 - mapped to GULP1, HBA1, and ITFG3 genes, respectively. The minor allele frequencies of rs148228241 (0.07) and rs8045544 (0.19) are rare or non-existent in non-African populations. Both rs8045544 and rs148228241 are significantly associated with the mean corpuscular hemoglobin concentration (MCHC). A lower MCHC is associated with alpha thalassaemia, resulting from deletions in HBA1 and HBA2 genes. Such deletions are prevalent in malaria-endemic regions of Africa due to their selective survival advantage. The rs6724428 variant is associated with skeletal functions, reflecting the link between glucose metabolism and bone mineral density.
Discussion: Our findings highlight the interplay between glucose metabolism, erythropoiesis, and skeletal health. The significant associations of HbA1c-variants with both skeletal function and MCHC underscore the potential of these variants to impact broader physiological processes. A large-scale study of African individuals will be essential to unravel genetic variants influencing HbA1c.
Copyright: © 2025 Soremekun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Estimating the health impact of menu calorie labelling policy and sugar-sweetened beverage taxation in two European countries: a microsimulation study
Get PDFAims: To estimate and compare the impacts of mandatory menu calorie labelling policy and sugar-sweetened beverage (SSB) taxation on reducing obesity prevalence, cardiovascular disease (CVD) mortality, and equity-related impacts, in Belgium and Germany.
Methods and results: We used microsimulation models over a 20-year simulation horizon (2022-2041). We modelled the impacts through assumed changes in energy intake due to consumer responses and food industry reformulation. Scenarios of partial (in 'large' out-of-home food businesses; ≥ 250 employees) and full (in all out-of-home food businesses) implementation for menu calorie labelling and different tax rates for SSBs (10%, 20%, 30%) were simulated. Compared with the counterfactual scenario, assuming effects on both consumer and industry behaviour, menu calorie labelling applied to all out-of-home food businesses was estimated to reduce obesity prevalence by 3.61 [95% uncertainty interval-UI: (2.78, 4.30)] and 4.28 [95% UI: (3.64, 5.06)] percentage points and prevent 1600 [95% UI: (400, 3800)] and 30 000 [95% UI: (10 000, 58 000)] CVD deaths in Belgium and Germany over 20 years, respectively. The 30% SSB tax was estimated to reduce obesity prevalence by 0.27 [95% UI: (0.17, 0.43)] and 0.27 [95% UI: (0.17, 0.39)] percentage points and postpone 2500 [95% UI: (800, 5200)] and 16 000 [95% UI: (7500, 28 000)] CVD deaths in Belgium and Germany, respectively. In both countries, SSB taxation had a larger impact on CVD deaths for lower (vs. higher) education groups, whereas menu calorie labelling prevented more CVD deaths for higher (vs. lower) education groups.
Conclusion: Menu calorie labelling and SSB taxation have substantial impacts on reducing obesity prevalence and preventing CVD deaths in Belgium and Germany. Implementing both policies will be important to tackle obesity and CVD burden
Effects of Visual Modality on Conversations with Interactive Digital Testimonies
Get PDFInteractive Digital Testimonies (IDTs) allow users to learn virtually about the life stories of contemporary witnesses as recounted by the witnesses themselves. Although several IDTs have been created in recent years, there is little empirical research on their effects on users. We investigated how different levels of visual modality (audio-only, audio-visual 2D, audio-visual stereoscopic 3D) affect user perception by conducting two separate mixed-methods studies: A 2x2 between-subjects study comparing audio-only with audio-visual 2D in in-person and online settings (n = 82) and a within-subjects study comparing audio-visual 2D with audio-visual stereoscopic 3D (n = 51). We found that audio-visual 2D improves user experience, immersion, and perceived authenticity over audio-only versions. Audio-visual 3D IDTs are more authentic and immersive than audio-visual 2D IDTs, however, this is diminished by a less comfortable interaction. Our findings broaden empirical research on user perception of realistic Embodied Conversational Agents and help guide future thanatosensitive designs
Multicenter Longitudinal Quality Assessment of MS-Based Proteomics in Plasma and Serum
Get PDFAdvancing MS-based proteomics toward clinical applications evolves around developing standardized start-to-finish and fit-for-purpose workflows for clinical specimens. Steps along the method design involve the determination and optimization of several bioanalytical parameters such as selectivity, sensitivity, accuracy, and precision. In a joint effort, eight proteomics laboratories belonging to the MSCoreSys initiative including the CLINSPECT-M, MSTARS, DIASyM, and SMART-CARE consortia performed a longitudinal round-robin study to assess the analysis performance of plasma and serum as clinically relevant samples. A variety of LC-MS/MS setups including mass spectrometer models from ThermoFisher and Bruker as well as LC systems from ThermoFisher, Evosep, and Waters Corporation were used in this study. As key performance indicators, sensitivity, precision, and reproducibility were monitored over time. Protein identifications range between 300 and 400 IDs across different state-of-the-art MS instruments, with timsTOF Pro, Orbitrap Exploris 480, and Q Exactive HF-X being among the top performers. Overall, 71 proteins are reproducibly detectable in all setups in both serum and plasma samples, and 22 of these proteins are FDA-approved biomarkers, which are reproducibly quantified (CV < 20% with label-free quantification). In total, the round-robin study highlights a promising baseline for bringing MS-based measurements of serum and plasma samples closer to clinical utility
Identifying Trends in Feature Attributions During Training of Neural Networks
Get PDFThis study investigates the evolving dynamics of commonly used feature attribution (FA) values during training of neural networks. As models transition from a state of high uncertainty to low uncertainty, we show that the features’ significance also changes, which is inline with the general learning theory of deep neural networks. During model training, we compute FA scores through Layer-wise Relevance Propagation (LRP) and Gradient-weighted Class Activation Mapping (Grad-CAM), which are selected for their efficiency and speed of computation. We summarize the attribution scores in terms of the sum of the absolute values of FA scores and their entropy. We further analyze these summary scores in relation to the models’ generalization capabilities. The analysis identifies trends where FA values increase in magnitude while entropy decreases during the training process, regardless of model generalization, suggesting independence of overfitting. This research offers a unique view on the application of FA methods in explainable artificial intelligence (XAI) and raises intriguing questions about their behavior across varying model architectures and datasets, which may have implications for future work combining XAI and uncertainty estimation in machine learning
AQP4-specific T cells determine lesion localization in the CNS in a model of NMOSD
Get PDFNeuromyelitis optica spectrum disorder (NMOSD) is a paradigmatic autoimmune disease of the central nervous system (CNS), in which the water channel protein Aquaporin-4 (AQP4) is targeted by a self-reactive immune response. While the immunopathology of human NMOSD is largely dependent on antibodies to astrocytic AQP4, the role of AQP4-specific T cells for the localization and quality of NMOSD lesions in the CNS is not known. Only recently, we established that thymic B cells express and present AQP4 in the context of MHC class II molecules to purge the naive T cell receptor repertoire of AQP4-specific clones. Here, we exploited this finding to investigate the lesion localization in the CNS of B cell conditional AQP4-deficient (Aqp4ΔB) mice, which harbor AQP4-specific precursors in their naive T cell repertoire and can be sensitized to mount a strong AQP4(201–220)-specific CD4+ T cell response. Sensitization of Aqp4ΔB mice with AQP4(201–220) was sufficient to induce clinical disease. The spatiotemporal lesion distribution and the glial cell response in AQP4(201–220)-induced experimental autoimmune encephalomyelitis (EAE) was compared to classical MOG(35–55)-induced EAE in Aqp4ΔB mice. In contrast to MOG-EAE, AQP4(201–220)-induced EAE was characterized by midline lesions in the brain, retinal pathology, and lesions at the grey matter/white matter border zone in the spinal cord. Therefore, we conclude that antigen-specific T cells dictate the localization of NMOSD-lesions in the CNS
Long-term associations between ambient air pollution and self-perceived health statusstudy: Results from the population-based KORA-Fit study
Get PDFBackground
Little is known about the association between air pollution and self-perceived health (including both health-related quality of life [HRQoL] and self-rated health [SRH]). The aim of this study was therefore to explore whether long-term air pollution exposure is associated with worse self-perceived health, as measured by different tools.
Methods
We used a land-use regression model to determine the annual average levels of particulate matter with a diameter <10 μm (PM10), coarse particles (PMcoarse), fine particles (PM2.5), fine particle absorbances (PM2.5abs), particle number concentration (PNC), ozone (O3), nitrogen dioxide (NO2), and nitrogen oxide (NOX) for geocoded residential addresses (2014–2015). Questionnaires and face-to-face interviews were used to collect HRQoL (measured using the European Quality of Life 5 Dimensions [EQ-5D] index and the European Quality of Life Visual Analogue Scale [EQ-VAS]) and SRH indicators (measured through two survey questions) (2018–2019) from participants of the Cooperative Health Research in the Region of Augsburg (KORA)-Fit study in Germany. We explored associations via generalized additive models, multinomial logistic regression, and logistic regression.
Results
We included 2610 participants with a mean age of 64.0 years in this cross-sectional study, of which 1428 (54.7%) were female. Each interquartile range (IQR) increase in O3 was associated with a reduced EQ-5D index value (% change of mean points and 95% confidence interval: -0.91% [-1.76; -0.06]). The average EQ-VAS score declined between -1.57% and -0.96% with each IQR increase in PM10, PMcoarse, PM2.5abs, PNC, NO2, and NOX. These pollutants were associated with increased occurrence of poor SRH, with odds ratios ranging from 1.24 to 2.67. PM2.5abs was linked to a higher likelihood of reporting a worse comparative SRH (2.59 [1.12; 5.99]). Body mass index and self-perceived stress modified these associations.
Conclusions
Long-term air pollution exposure was associated with poor self-perceived health, presenting as lower HRQoL and higher odds of poor SRH. Single-item indicators measuring self-perceived health status may work better than multi-dimensional indicators
Linking higher amyloid beta 1‐38 (Aβ(1‐38)) levels to reduced Alzheimer's disease progression risk
Get PDFIntroduction: The beneficial effects of amyloid beta 1-38, or Aβ(1-38), onAlzheimer’s disease (AD) progression in humans in vivo remain controversial. Weinvestigated AD patients’ cerebrospinal fluid (CSF) Aβ(1-38) and AD progression.
Methods: Cognitive function and diagnostic change were assessed annually for3 years in 177 Aβ-positive participants with subjective cognitive decline (SCD),mild cognitive impairment (MCI), and dementia from the German Center for Neu-rodegenerative Diseases (DZNE) longitudinal cognitive impairment and dementiastudy (DELCODE) cohort using the Mini-Mental State Examination (MMSE), Pre-clinical Alzheimer’s Cognitive Composite (PACC), Clinical Dementia Rating (CDR),and National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.Mixed linear and Cox regression analyses were conducted. CSF was collected atbaseline.
Results: Higher Aβ(1-38) levels were associated with slower PACC (p = 0.001) andslower CDR Sum of Boxes (CDR-SB) (p = 0.002) but not MMSE decline. Including Aβ(1-40) beyond Aβ(1-38) in the model confirmed an association of Aβ(1-38) with slowerPACC decline (p = 0.005), but not with CDR-SB or MMSE decline. In addition, higherAβ(1-38) baseline levels were associated with a reduced dementia conversion risk.
Discussion: Further research is needed to understand the role of Aβ(1-38) in AD andits potential for future therapeutic strategies
OoTrap: enhancing oocyte collection and maturation with a field-deployable fluidic device
Get PDFAssisted reproductive technologies (ART) are pivotal for contemporary reproductive medicine and species conservation. However, the manual handling required in these processes introduces stress that can compromise oocyte and embryo quality. This study introduces OoTrap, a novel fluidic device designed to streamline ART workflows by facilitating the capture and maturation of oocytes in a compact unit. The device also reintroduces mechanical forces similar to those in the in vivo environment, which are often missing in conventional systems. OoTrap operates in both static and perfusion-based modes, offering flexibility and optimal conditions for oocyte maturation. Notably, OoTrap achieved higher in vitro maturation (IVM) rates under perfusion, produced oocytes with fewer chromosomal abnormalities, and maintained spindle morphology integrity. The incorporation of a heating system and a 3D-printed syringe pump enabled IVM outside the incubator, making OoTrap suitable for field applications. The results highlight the potential of OoTrap to enhance ART outcomes by reducing manual handling, providing a controlled microenvironment, and offering a practical solution for field-based ART applications
Astrocyte heterogeneity reveals region-specific astrogenesis in the white matter
Get PDFAstrocyte heterogeneity has been well explored, but our understanding of white matter (WM) astrocytes and their distinctions from gray matter (GM) astrocytes remains limited. Here, we compared astrocytes from cortical GM and WM/corpus callosum (WM/CC) using single-cell RNA sequencing and spatial transcriptomics of the murine forebrain. The comparison revealed similarities but also significant differences between WM and GM astrocytes, including cytoskeletal and metabolic hallmarks specific to WM astrocytes with molecular properties also shared with human WM astrocytes. When we compared murine astrocytes from two different WM regions, the cortex and cerebellum, we found that they exhibited distinct, region-specific molecular properties, with the cerebellum lacking, for example, a specific cluster of WM astrocytes expressing progenitor and proliferation genes. Functional experiments confirmed astrocyte proliferation in the WM/CC, but not in the cerebellar WM, suggesting that the WM/CC may be a source of continued astrogenesis