Publications by authors named "Judith Zandstra"

5 Publications

  • Page 1 of 1

Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration.

Am J Hum Genet 2021 08 13;108(8):1367-1384. Epub 2021 Jul 13.

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525EX, the Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525GA, the Netherlands. Electronic address:

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10), FHR-2 (p = 1.47 × 10), FHR-3 (p = 1.05 × 10) and FHR-4A (p = 1.22 × 10) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10 and p = 2.81 × 10, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387287PMC
August 2021

Future Biomarkers for Infection and Inflammation in Febrile Children.

Front Immunol 2021 17;12:631308. Epub 2021 May 17.

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Amsterdam, Netherlands.

Febrile patients, suffering from an infection, inflammatory disease or autoimmunity may present with similar or overlapping clinical symptoms, which makes early diagnosis difficult. Therefore, biomarkers are needed to help physicians form a correct diagnosis and initiate the right treatment to improve patient outcomes following first presentation or admittance to hospital. Here, we review the landscape of novel biomarkers and approaches of biomarker discovery. We first discuss the use of current plasma parameters and whole blood biomarkers, including results obtained by RNA profiling and mass spectrometry, to discriminate between bacterial and viral infections. Next we expand upon the use of biomarkers to distinguish between infectious and non-infectious disease. Finally, we discuss the strengths as well as the potential pitfalls of current developments. We conclude that the use of combination tests, using either protein markers or transcriptomic analysis, have advanced considerably and should be further explored to improve current diagnostics regarding febrile infections and inflammation. If proven effective when combined, these biomarker signatures will greatly accelerate early and tailored treatment decisions.
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http://dx.doi.org/10.3389/fimmu.2021.631308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165271PMC
September 2021

Biomarkers to predict infection and infection-related complications during chemotherapy-induced neutropenia in acute myeloid leukaemia: a pilot study.

Br J Haematol 2021 06 8;193(5):1008-1012. Epub 2021 Apr 8.

Department of Blood Cell Research, Division Research and Landsteiner Laboratory of Amsterdam UMC, Sanquin Blood Supply, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1111/bjh.17422DOI Listing
June 2021

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood.

Front Pediatr 2020 22;8:355. Epub 2020 Jul 22.

Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.

Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication-the development of coronary artery aneurysms (CAA)-can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients ( = 48) from patients with infection ( = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients ( = 26) from those with infections ( = 150), with an AUC of 0.78. The second validation cohort of acute KD patients ( = 25) and febrile controls ( = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.
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http://dx.doi.org/10.3389/fped.2020.00355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388698PMC
July 2020

Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1.

Nat Med 2019 06 13;25(6):988-1000. Epub 2019 May 13.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.
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http://dx.doi.org/10.1038/s41591-019-0440-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642642PMC
June 2019
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