Martin Golebiewski

About Martin Golebiewski:
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LHA ID: 824HFXG5CA-9

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ORCID: https://orcid.org/0000-0002-8683-7084

Joined: 6th May 2020

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NFDI4Health - TA3 Services

TA3 focusses on the services, service enabling tools, and software that NFDI4Health will provide to the user community. Services and tools that will be developed or advanced during the project will be published as open source software.

Programme: NFDI - German National Research Data Infrastructure

Public web page: https://www.nfdi4health.de/en/about-us/task-areas/ta3-services.html

NFDI4Health: inactive since

NFDI4Health - the National Research Data Infrastructure for Personal Health Data - deals with data generated in clinical trials, epidemiological and public health studies. The collection and analysis of these data on health and disease status and important factors influencing it are an essential component for the development of new therapies, comprehensive care approaches and preventive measures in a modern health care system. Although these data already meet high content quality standards, they ...

Programme: NFDI - German National Research Data Infrastructure

Public web page: https://www.nfdi4health.de/en

Dynamics of cytokines, immune cell counts and disease severity in patients with community-acquired pneumonia - Unravelling potential causal relationships
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Community acquired pneumonia (CAP) is a severe and often rapidly deteriorating disease. To better understand its dynamics and potential causal relationships, we analyzed time series data of …f cytokines, blood and clinical parameters in hospitalized CAP patients. METHODS Time series data of 10 circulating cytokines, blood counts and clinical parameters were related to baseline characteristics of 403 CAP patients using univariate mixed models. Bivariate mixed models were applied to analyze correlations between the time series. To identify potential causal relationships, we inferred cross-lagged relationships between pairs of parameters using latent curve models with structured residuals. RESULTS IL-6 levels decreased faster over time in younger patients (Padj = 0.06). IL-8, VCAM-1, and IL-6 correlated strongly with disease severity as assessed by the sequential organ failure assessment (SOFA) score (r = 0.49, 0.48, 0.46, respectively; all Padj \textless 0.001). IL-6 and bilirubin correlated with respect to their mean levels and slopes over time (r = 0.36 and r = 0.46, respectively; Padj \textless 0.001). A number of potential causal relationships were identified, e.g., a negative effect of ICAM-1 on MCP-1, or a positive effect of the level of creatinine on the subsequent VCAM-1 concentration (P \textless 0.001). CONCLUSIONS These results suggest that IL-6 trajectories of CAP patients are associated with age and run parallel to bilirubin levels. The time series analysis also unraveled directed, potentially causal relationships between cytokines, blood parameters and clinical outcomes. This will facilitate the development of mechanistic models of CAP, and with it, improvements in treatment or surveillance strategies for this disease. TRIAL REGISTRATION clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.

Authors: Maciej Rosolowski, Volker Oberle, Peter Ahnert, Petra Creutz, Martin Witzenrath, Michael Kiehntopf, Markus Loeffler, Norbert Suttorp, Markus Scholz

Date Published: 1st Dec 2020

Publication Type: Journal article

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND PURPOSE Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, …, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. METHODS Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. RESULTS In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (NBEAL), 10q23.1 (TSPAN14/FAM231A), and 10q24.33 (SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 (NOS3) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. CONCLUSIONS Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Authors: Nicola J. Armstrong, Karen A. Mather, Muralidharan Sargurupremraj, Maria J. Knol, Rainer Malik, Claudia L. Satizabal, Lisa R. Yanek, Wei Wen, Vilmundur G. Gudnason, Nicole D. Dueker, Lloyd T. Elliott, Edith Hofer, Joshua Bis, Neda Jahanshad, Shuo Li, Mark A. Logue, Michelle Luciano, Markus Scholz, Albert V. Smith, Stella Trompet, Dina Vojinovic, Rui Xia, Fidel Alfaro-Almagro, David Ames, Najaf Amin, Philippe Amouyel, Alexa S. Beiser, Henry Brodaty, Ian J. Deary, Christine Fennema-Notestine, Piyush G. Gampawar, Rebecca Gottesman, Ludovica Griffanti, Clifford R. Jack, Mark Jenkinson, Jiyang Jiang, Brian G. Kral, John B. Kwok, Leonie Lampe, David C M Liewald, Pauline Maillard, Jonathan Marchini, Mark E. Bastin, Bernard Mazoyer, Lukas Pirpamer, José Rafael Romero, Gennady V. Roshchupkin, Peter R. Schofield, Matthias L. Schroeter, David J. Stott, Anbupalam Thalamuthu, Julian Trollor, Christophe Tzourio, Jeroen van der Grond, Meike W. Vernooij, Veronica A. Witte, Margaret J. Wright, Qiong Yang, Zoe Morris, Siggi Siggurdsson, Bruce Psaty, Arno Villringer, Helena Schmidt, Asta K. Haberg, Cornelia M. van Duijn, J. Wouter Jukema, Martin Dichgans, Ralph L. Sacco, Clinton B. Wright, William S. Kremen, Lewis C. Becker, Paul M. Thompson, Thomas H. Mosley, Joanna M. Wardlaw, M. Arfan Ikram, Hieab H. H. Adams, Sudha Seshadri, Perminder S. Sachdev, Stephen M. Smith, Lenore Launer, William Longstreth, Charles DeCarli, Reinhold Schmidt, Myriam Fornage, Stephanie Debette, Paul A. Nyquist

Date Published: 1st Jul 2020

Publication Type: Journal article

Markov State Modelling of Disease Courses and Mortality Risks of Patients with Community-Acquired Pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

Community-acquired pneumonia (CAP) is one of the most frequent infectious diseases worldwide, with high lethality. Risk evaluation is well established at hospital admission, and re-evaluation is advised … for patients at higher risk. However, severe disease courses may develop from all levels of severity. We propose a stochastic continuous-time Markov model describing daily development of time courses of CAP severity. Disease states were defined based on the Sequential Organ Failure Assessment (SOFA) score. Model calibration was based on longitudinal data from 2838 patients with a primary diagnosis of CAP from four clinical studies (PROGRESS, MAXSEP, SISPCT, VISEP). We categorized CAP severity into five disease states and estimated transition probabilities for CAP progression between these states and corresponding sojourn times. Good agreement between model predictions and clinical data was observed. Time courses of mortality were correctly predicted for up to 28 days, including validation with patient data not used for model calibration. We conclude that CAP disease course follows a Markov process, suggesting the necessity of daily monitoring and re-evaluation of patient’s risk. Our model can be used for regular updates of risk assessments of patients and could improve the design of clinical trials by estimating transition rates for different risk groups.

Authors: Jens Przybilla, Peter Ahnert, Holger Bogatsch, Frank Bloos, Frank M. Brunkhorst, Critical Care Trials Group SepNet, Study Group Progress, Michael Bauer, Markus Loeffler, Martin Witzenrath, Norbert Suttorp, Markus Scholz

Date Published: 1st Feb 2020

Publication Type: Journal article

Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving …g lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis. METHODS The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing L-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13). RESULTS In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 \pm 0.89 vs. 3.29 \pm 2.34, mean \pm SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 \pm 1.17 vs. 7.31 \pm 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury. CONCLUSIONS Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia. : WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Pneumonia, sepsis, and immune dysregulation cause morbidity and mortalityC5a is a component of the complement system and a proinflammatory mediator that modulates the innate immune response in critical illnessDisruption of the C5a receptor axis with antibodies or antagonists was previously protective in various animal sepsis models WHAT THIS ARTICLE TELLS US THAT IS NEW: In hospitalized patients with community-acquired pneumonia, serum C5a concentrations were 1.4-fold higher compared to healthy subjectsIn two mouse models of pneumonia and sepsis, NOX-D19, a C5a-neutralizing L-RNA aptamer, caused lower pulmonary hyperpermeability and sepsis-related acute liver injury.

Authors: Holger Müller-Redetzky, Ute Kellermann, Sandra-Maria Wienhold, Birgitt Gutbier, Jasmin Lienau, Katharina Hellwig, Katrin Reppe, Eleftheria Letsiou, Thomas Tschernig, Markus Scholz, Peter Ahnert, Christian Maasch, Kai Hoehlig, Sven Klussmann, Axel Vater, Theresa C. Firsching, Judith Hoppe, Norbert Suttorp, Martin Witzenrath

Date Published: 2020

Publication Type: Journal article

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Genetical Statistics and Systems Biology

Abstract (Expand)

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses … of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Authors: Nora Franceschini, Claudia Giambartolomei, Paul S. de Vries, Chris Finan, Joshua C. Bis, Rachael P. Huntley, Ruth C. Lovering, Salman M. Tajuddin, Thomas W. Winkler, Misa Graff, Maryam Kavousi, Caroline Dale, Albert V. Smith, Edith Hofer, Elisabeth M. van Leeuwen, Ilja M. Nolte, Lingyi Lu, Markus Scholz, Muralidharan Sargurupremraj, Niina Pitkänen, Oscar Franzén, Peter K. Joshi, Raymond Noordam, Riccardo E. Marioni, Shih-Jen Hwang, Solomon K. Musani, Ulf Schminke, Walter Palmas, Aaron Isaacs, Adolfo Correa, Alan B. Zonderman, Albert Hofman, Alexander Teumer, Amanda J. Cox, André G. Uitterlinden, Andrew Wong, Andries J. Smit, Anne B. Newman, Annie Britton, Arno Ruusalepp, Bengt Sennblad, Bo Hedblad, Bogdan Pasaniuc, Brenda W. Penninx, Carl D. Langefeld, Christina L. Wassel, Christophe Tzourio, Cristiano Fava, Damiano Baldassarre, Daniel H. O’Leary, Daniel Teupser, Diana Kuh, Elena Tremoli, Elmo Mannarino, Enzo Grossi, Eric Boerwinkle, Eric E. Schadt, Erik Ingelsson, Fabrizio Veglia, Fernando Rivadeneira, Frank Beutner, Ganesh Chauhan, Gerardo Heiss, Harold Snieder, Harry Campbell, Henry Völzke, Hugh S. Markus, Ian J. Deary, J. Wouter Jukema, Jacqueline de Graaf, Jacqueline Price, Janne Pott, Jemma C. Hopewell, Jingjing Liang, Joachim Thiery, Jorgen Engmann, Karl Gertow, Kenneth Rice, Kent D. Taylor, Klodian Dhana, Lambertus A. L. M. Kiemeney, Lars Lind, Laura M. Raffield, Lenore J. Launer, Lesca M. Holdt, Marcus Dörr, Martin Dichgans, Matthew Traylor, Matthias Sitzer, Meena Kumari, Mika Kivimaki, Mike A. Nalls, Olle Melander, Olli Raitakari, Oscar H. Franco, Oscar L. Rueda-Ochoa, Panos Roussos, Peter H. Whincup, Philippe Amouyel, Philippe Giral, Pramod Anugu, Quenna Wong, Rainer Malik, Rainer Rauramaa, Ralph Burkhardt, Rebecca Hardy, Reinhold Schmidt, Renée de Mutsert, Richard W. Morris, Rona J. Strawbridge, S. Goya Wannamethee, Sara Hägg, Sonia Shah, Stela McLachlan, Stella Trompet, Sudha Seshadri, Sudhir Kurl, Susan R. Heckbert, Susan Ring, Tamara B. Harris, Terho Lehtimäki, Tessel E. Galesloot, Tina Shah, Ulf de Faire, Vincent Plagnol, Wayne D. Rosamond, Wendy Post, Xiaofeng Zhu, Xiaoling Zhang, Xiuqing Guo, Yasaman Saba, Abbas Dehghan, Adrie Seldenrijk, Alanna C. Morrison, Anders Hamsten, Bruce M. Psaty, Cornelia M. van Duijn, Deborah A. Lawlor, Dennis O. Mook-Kanamori, Donald W. Bowden, Helena Schmidt, James F. Wilson, James G. Wilson, Jerome I. Rotter, Joanna M. Wardlaw, John Deanfield, Julian Halcox, Leo-Pekka Lyytikäinen, Markus Loeffler, Michele K. Evans, Stéphanie Debette, Steve E. Humphries, Uwe Völker, Vilmundur Gudnason, Aroon D. Hingorani, Johan L. M. Björkegren, Juan P. Casas, Christopher J. O’Donnell

Date Published: 1st Dec 2018

Publication Type: Journal article

Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

RATIONALE During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2-activation by Angiopoietin-1 reduces, while Tie2-blockade by Angiopoietin-2 increases …s inflammation and permeability during sepsis. The role of Angiopoietin-1/-2 in pneumonia remains unidentified. OBJECTIVES To investigate the prognostic and pathogenetic impact of Angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia. METHODS Serum Angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n=148, n=395). Human post mortem lung tissue, pneumolysin- or Angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated. MEASUREMENTS AND MAIN RESULTS In pneumonia patients, decreased serum Angiopoietin-1 and increased Angiopoietin-2 levels were observed as compared to healthy subjects. Higher Angiopoietin-2 serum levels were found in community-acquired pneumonia patients who died within 28 days after diagnosis compared to survivors. ROC analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment and length of hospital stay if combined with Angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial Angiopoietin-2 release, Angiopoietin-2 increased endothelial permeability, and Angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with Angiopoietin-2-knockdown showed reduced permeability upon pneumolysin stimulation. Increased pulmonary Angiopoietin-2 and reduced Angiopoietin-1 mRNA expression were observed in S. pneumoniae infected mice. Finally, Angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia. CONCLUSIONS These data suggest a central role of Angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased Angiopoietin-2 serum levels predicted mortality and length of hospital stay, and Angiopoietin-1 may provide a therapeutic target for severe pneumonia.

Authors: Birgitt Gutbier, Anne-Kathrin Neuhauß, Katrin Reppe, Carolin Ehrler, Ansgar Santel, Jörg Kaufmann, Markus Scholz, Norbert Weissmann, Lars Morawietz, Timothy J. Mitchell, Stefano Aliberti, Stefan Hippenstiel, Norbert Suttorp, Martin Witzenrath

Date Published: 15th Jul 2018

Publication Type: Journal article

Urine Biomarkers of Tubular Renal Cell Damage for the Prediction of Acute Kidney Injury After Cardiac Surgery-A Pilot Study
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE To evaluate the perioperative course of urine levels of the renal damage biomarkers tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) …) and to evaluate the predictive value of elevated TIMP-2 \times IGFBP7 concentrations to predict acute kidney injury (AKI) early after cardiac on-pump surgery. DESIGN Prospective, observational cohort study. SETTING University hospital. PARTICIPANTS The study comprised 110 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) between January and March 2014. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Urinary TIMP-2 \times IGFBP7 levels were quantified using a commercially available kit at the following measurement points: before surgery, 1 hour after starting CPB, 4 hours after weaning from CPB, and 24 hours after weaning from CPB (time points 1-4). Postoperative AKI was defined according to Kidney Disease Improving Global Outcomes criteria. AKI after cardiac surgery was diagnosed in 9 patients (8%). The perioperative course of TIMP-2 \times IGFBP7 was significantly different in patients with and without postoperative AKI (p \textless 0.001). TIMP-2 \times IGFBP7 levels were significantly higher in patients with AKI 1 hour after CPB start and 24 hours after weaning from CPB (p \textless 0.05). TIMP-2 \times IGFBP7 levels \textgreater0.40 (ng/mL)(2)/1,000 measured at 1 hour after starting CPB were found to be the optimal cut-off, with a sensitivity of 0.778 and a specificity of 0.641. The negative predictive value was 0.972. CONCLUSIONS Urine levels of TIMP-2 \times IGFBP7 are predictive for AKI at an early time point (1 hour after starting CPB). Renal damage biomarkers such as TIMP-2 and IGFBP7 might be recommended as a supplement to traditionally used criteria of AKI prediction.

Authors: Tanja Mayer, Daniel Bolliger, Markus Scholz, Oliver Reuthebuch, Michael Gregor, Patrick Meier, Martin Grapow, Manfred D. Seeberger, Jens Fassl

Date Published: 1st Dec 2017

Publication Type: Journal article

A Biomathematical Model of Pneumococcal Lung Infection and Antibiotic Treatment in Mice
Genetical Statistics and Systems Biology

Abstract (Expand)

Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due … to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future.

Authors: Sibylle Schirm, Peter Ahnert, Sandra Wienhold, Holger Mueller-Redetzky, Geraldine Nouailles-Kursar, Markus Loeffler, Martin Witzenrath, Markus Scholz

Date Published: 19th May 2016

Publication Type: Journal article

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnThis study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.\backslashr\backslashnBACKGROUND\backslashr\backslashnHigher … circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.\backslashr\backslashnMETHODS\backslashr\backslashnWe conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.\backslashr\backslashnRESULTS\backslashr\backslashnPLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnReducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.

Authors: Michael V. Holmes, Tabassome Simon, Holly J. Exeter, Lasse Folkersen, Folkert W. Asselbergs, Montse Guardiola, Jackie A. Cooper, Jutta Palmen, Jaroslav A. Hubacek, Kathryn F. Carruthers, Benjamin D. Horne, Kimberly D. Brunisholz, Jessica L. Mega, Erik P A van Iperen, Mingyao Li, Maarten Leusink, Stella Trompet, Jeffrey J W Verschuren, G. Kees Hovingh, Abbas Dehghan, Christopher P. Nelson, Salma Kotti, Nicolas Danchin, Markus Scholz, Christiane L. Haase, Dietrich Rothenbacher, Daniel I. Swerdlow, Karoline B. Kuchenbaecker, Eleonora Staines-Urias, Anuj Goel, Ferdinand van ’t Hooft, Karl Gertow, Ulf de Faire, Andrie G. Panayiotou, Elena Tremoli, Damiano Baldassarre, Fabrizio Veglia, Lesca Miriam Holdt, Frank Beutner, Ron T. Gansevoort, Gerjan J. Navis, Irene Mateo Leach, Lutz P. Breitling, Hermann Brenner, Joachim Thiery, Dhayana Dallmeier, Anders Franco-Cereceda, Jolanda M A Boer, Jeffrey W. Stephens, Marten H. Hofker, Alain Tedgui, Albert Hofman, André G. Uitterlinden, Vera Adamkova, Jan Pitha, N. Charlotte Onland-Moret, Maarten J. Cramer, Hendrik M. Nathoe, Wilko Spiering, Olaf H. Klungel, Meena Kumari, Peter H. Whincup, David A. Morrow, Peter S. Braund, Alistair S. Hall, Anders G. Olsson, Pieter A. Doevendans, Mieke D. Trip, Martin D. Tobin, Anders Hamsten, Hugh Watkins, Wolfgang Koenig, Andrew N. Nicolaides, Daniel Teupser, Ian N M Day, John F. Carlquist, Tom R. Gaunt, Ian Ford, Naveed Sattar, Sotirios Tsimikas, Gregory G. Schwartz, Debbie A. Lawlor, Richard W. Morris, Manjinder S. Sandhu, Rudolf Poledne, Anke H Maitland-van der Zee, Kay-Tee Khaw, Brendan J. Keating, Pim van der Harst, Jackie F. Price, Shamir R. Mehta, Salim Yusuf, Jaqueline C M Witteman, Oscar H. Franco, J. Wouter Jukema, Peter de Knijff, Anne Tybjaerg-Hansen, Daniel J. Rader, Martin Farrall, Nilesh J. Samani, Mika Kivimaki, Keith A A Fox, Steve E. Humphries, Jeffrey L. Anderson, S. Matthijs Boekholdt, Tom M. Palmer, Per Eriksson, Guillaume Paré, Aroon D. Hingorani, Marc S. Sabatine, Ziad Mallat, Juan P. Casas, Philippa J. Talmud

Date Published: 1st Nov 2013

Publication Type: Journal article

Harmonization of growth hormone measurements with different immunoassays by data adjustment
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe aim of our study was to evaluate the between-assay variability of commercially available immunoassays for the measurement of human growth hormone (hGH). In addition, … we asked whether the comparability of the diagnosis of childhood onset growth hormone deficiency could be improved by adjusting hGH results by statistical methods, such as linear regression, conversion factors, and quantile transformation.\backslashr\backslashnMETHODS\backslashr\backslashnIn archived sera from 312 children and adolescents (age: 17 days-17 years) hGH values between 0.01 and 16.5 ng/mL were determined by using the following immunoassays: AutoDELFIA (PerkinElmer), BC-IRMA (Beckman-Coulter), ELISA (Mediagnost), IMMULITE 2000 (Siemens), iSYS (IDS), Liaison (DiaSorin), UniCel DxI 800 Access (BeckmanCoulter) and {\textquotedblIn house{\textquotedbl-RIA (Tübingen).\backslashr\backslashnRESULTS\backslashr\backslashnThe assays differed in median hGH concentrations by as much as 5.44 ng/mL (Immulite), and as little as 2.67 ng/mL (BC-IRMA). The mean difference between assays ranged from 0.35 to 2.71 ng/mL, whereas several samples displayed differences up to 11.4 ng/mL. The best correlation (r=0.992) was found between AutoDELFIA and Liasion, the lowest (r=0.864) was between an in-house RIA and iSYS. The between-assay CV (mean \pm SD) of values within the cut-off range was 24.3% \pm 7.4%, resulting in an assay-dependent diagnosis of growth hormone deficiency (GHD) in more than 27% of patients. Yet, adjustment of this data by linear regression or a conversion factor reduced the CV below 14%, and the ratio of assay-dependent diagnoses below 8%. Using quantile transformation, the CV and ratio were reduced to 11.4% and \textless1%, respectively.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnhGH measurements using different assays vary significantly. Linear regression, conversion factors, or particularly quantile transformation are useful tools to improve comparability in the diagnostic procedure for the confirmation of GHD in childhood and adolescence.

Authors: Anne Müller, Markus Scholz, Oliver Blankenstein, Gerhard Binder, Roland Pfäffle, Antje Körner, Wieland Kiess, Annegret Heider, Martin Bidlingmaier, Joachim Thiery, Jürgen Kratzsch

Date Published: 2011

Publication Type: Journal article

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