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- van der Harst, Pim, et al.
(author)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Journal article (peer-reviewed)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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- Sánchez Brotons, Alejandro, et al.
(author)
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Pipelines and Systems for Threshold-Avoiding Quantification of LC-MS/MS Data
- 2021
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In: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 93:32, s. 11215-11224
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Journal article (peer-reviewed)abstract
- The accurate processing of complex liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) data from biological samples is a major challenge for metabolomics, proteomics, and related approaches. Here, we present the pipelines and systems for threshold-avoiding quantification (PASTAQ) LC-MS/MS preprocessing toolset, which allows highly accurate quantification of data-dependent acquisition LC-MS/MS datasets. PASTAQ performs compound quantification using single-stage (MS1) data and implements novel algorithms for high-performance and accurate quantification, retention time alignment, feature detection, and linking annotations from multiple identification engines. PASTAQ offers straightforward parameterization and automatic generation of quality control plots for data and preprocessing assessment. This design results in smaller variance when analyzing replicates of proteomes mixed with known ratios and allows the detection of peptides over a larger dynamic concentration range compared to widely used proteomics preprocessing tools. The performance of the pipeline is also demonstrated in a biological human serum dataset for the identification of gender-related proteins.
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- Tigchelaar, Celien, et al.
(author)
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Cerebrospinal fluid and plasma concentrations of the inflammatory marker soluble CD27 in a large surgical population
- 2024
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In: iScience. - : Elsevier. - 2589-0042. ; 27:6
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Journal article (peer-reviewed)abstract
- Introduction: Soluble CD27 (sCD27) has the potential to serve as a biomarker for diseases involving immune system dysfunction. To inform interpretation of assay results, reference values are needed. So far, analysis of cerebrospinal fluid (CSF) sCD27 has mostly been performed in cohorts of patients with neuroinflammatory disorders, and general control data is missing. The aim of this study was therefore to determine reference ranges and to investigate the influence of factors such as age, comorbidity, blood-CSF-barrier (BCB) function (as assessed by the CSF/plasma albumin quotient (Qalb)) and inflammatory status markers, on CSF and plasma sCD27 concentrations in a relatively neurologically healthy surgical population. Methods: CSF and blood were collected from 486 patients undergoing spinal anaesthesia for elective surgery. Patient demographics, clinical data and the results of routine laboratory analyses were analysed for associations with sCD27 levels in CSF and plasma using a univariable and multivariable model. A healthy sub-cohort was selected based on an American Society of Anesthesiologists (ASA) physical status of I or II (healthy patient or with mild systemic disease), and inter alia, no history of cancer, immunological or neurological disorders, heavy tobacco use, or alcohol abuse. For the whole cohort, and the subpopulation of healthy patients we calculated reference intervals as the central 95% of the data.Results: In the total study group (age range 18 – 92 years, 57% male), median [range] CSF sCD27 concentration was 163 [<50 to 7474] pg/mL and median [range] plasma sCD27 concentration was 4624 [1830 to >400,000] pg/mL. In a multivariable model, plasma sCD27 concentration, age and Qalb were identified as most important for explaining the variability of CSF sCD27 levels. Reference sCD27 concentration intervals in the healthy sub-cohort were < 50 pg/mL – 419 pg/mL for CSF (n=125) and 2344 – 36422 pg/mL for plasma (n=158). Conclusions: Our data from a large group of patients reflecting a broad selection from the general population show that CSF sCD27 concentrations correlate with age and Qalb. These findings provide a solid foundation for interpreting sCD27 as clinical biomarker against a background of multiple socio-demographic and physiological aspects that may influence levels. Further studies to establish clinical CSF sCD27 cut-offs for central nervous system diseases should also account for the influence of age and blood-CSF-barrier function.
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4. |
- Timmers, Elze R., et al.
(author)
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Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients
- 2021
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In: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 91, s. 48-54
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Journal article (peer-reviewed)abstract
- Introduction: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations. Methods: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites. Results: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (rs = −0.3, p < 0.01), depression (rs = −0.3, p < 0.01) and fatigue (rs = −0.2, p = 0.04). Conclusion: This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.
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