TY - JOUR
T1 - Association between genetic variants of the cholinergic system and postoperative delirium and cognitive dysfunction in elderly patients
AU - Heinrich, Maria
AU - Sieg, Miriam
AU - Kruppa, Jochen
AU - Nürnberg, Peter
AU - Schreier, Peter H
AU - Heilmann-Heimbach, Stefanie
AU - Hoffmann, Per
AU - Nöthen, Markus M
AU - Janke, Jürgen
AU - Pischon, Tobias
AU - Slooter, Arjen J C
AU - Winterer, Georg
AU - Spies, Claudia D
N1 - Funding Information:
The authors would like to thank Konstanze Scheurer (Charité-Universitätsmedizin Berlin) for the administrative support with study coordination and management. Judy Veldhuijzen (UMC Utrecht), Antje Kraft (Charité Universitätsmedizin Berlin), Simone Kühn (University of Hamburg) and Insa Feinkohl (Max-Delbrück Center Berlin) provided additional neuropsychological expertise. Kathrin Scholtz supported the study as the clinical monitor. Henning Krampe supported the study by recruiting and supervising students for neuropsychological testing. Data management was provided by Olaf Bender and Alexander Krannich at Koordininierungszentrum für Klinische Studien (KKS Berlin) supported by Pharmaimage Biomarkers Solutions GmbH. We thank our team of investigators, medical doctoral students and study nurses: Alissa Wolf, Fatima Yürek, Daniel Hadzidiakos, Friedrich Borchers, Rudolf Mörgeli, Anika Müller, Ilse Kant, Simone van Montfort, Gunnar Lachmann, Anika Alon, Sina Rosenblender, Tuba Aslan, Markus Laubach, Felix Müller, Emmanuel Keller, Eleftheria Papadaki, Saya Speidel, Bennet Borak, Steffi Herferth, Johannes Lange, Mario Lamping, Helene Michler, Juliane Dörfler, Anton Jacobshagen, Petra Kozma, Marinus Fislage, Wolf Rüdiger Brockhaus, Luisa Rothe, Pola Neuling, Ken-Dieter Michel, Zdravka Bosancic, Firas Nosirat, Maryam Kurpanik, Sophia Kuenz, Lukas Roediger, Irene Mergele, Anja Nottbrock, Leopold Rupp, Marie Graunke, and Victoria Windmann. The authors further wish to thank the team of the student and interns of the Department of Anesthesiology at the Charité-Universitätsmedizin Berlin. We also thank Sarah Moreno Garcia for DNA preparation and Biobank management. Stefan Mundlos provided additional expertise for genetic analyses within the BIH-Charité Junior Clinician Scientist Program. Maria Heinrich is participant in the BIH-Charité Digital Clinician Scientist Program funded by the Charité –Universitätsmedizin Berlin and the Berlin Institute of Health. This program was initiated and led by Prof. Dr. Duska Dragun to enable resident physicians to pursue a career in digital health and academic research. With great sadness we have received the news that Prof. Dragun passed away on December 28th of 2020. This publication is dedicated to her as a mentor, role model and stellar scientist.
Funding Information:
Open Access funding enabled and organized by Projekt DEAL. This work was conducted with support of the European Union Seventh Framework Programme [FP7/2007–2013] as part of the BioCog project (Biomarker Development for Postoperative Cognitive Impairment in the Elderly), under grant Agreement N° 602461. Markus M. Nöthen is a member of the DFG-funded Excellence Cluster ImmunoSensation2 (EXC 2151 – 390873048). The sponsor had no influence on the study design, data collection, analysis or interpretation of data, nor was it at any point involved in the manuscript development.
Funding Information:
The authors would like to thank Konstanze Scheurer (Charité-Universitätsmedizin Berlin) for the administrative support with study coordination and management. Judy Veldhuijzen (UMC Utrecht), Antje Kraft (Charité Universitätsmedizin Berlin), Simone Kühn (University of Hamburg) and Insa Feinkohl (Max-Delbrück Center Berlin) provided additional neuropsychological expertise. Kathrin Scholtz supported the study as the clinical monitor. Henning Krampe supported the study by recruiting and supervising students for neuropsychological testing. Data management was provided by Olaf Bender and Alexander Krannich at Koordininierungszentrum für Klinische Studien (KKS Berlin) supported by Pharmaimage Biomarkers Solutions GmbH. We thank our team of investigators, medical doctoral students and study nurses: Alissa Wolf, Fatima Yürek, Daniel Hadzidiakos, Friedrich Borchers, Rudolf Mörgeli, Anika Müller, Ilse Kant, Simone van Montfort, Gunnar Lachmann, Anika Alon, Sina Rosenblender, Tuba Aslan, Markus Laubach, Felix Müller, Emmanuel Keller, Eleftheria Papadaki, Saya Speidel, Bennet Borak, Steffi Herferth, Johannes Lange, Mario Lamping, Helene Michler, Juliane Dörfler, Anton Jacobshagen, Petra Kozma, Marinus Fislage, Wolf Rüdiger Brockhaus, Luisa Rothe, Pola Neuling, Ken-Dieter Michel, Zdravka Bosancic, Firas Nosirat, Maryam Kurpanik, Sophia Kuenz, Lukas Roediger, Irene Mergele, Anja Nottbrock, Leopold Rupp, Marie Graunke, and Victoria Windmann. The authors further wish to thank the team of the student and interns of the Department of Anesthesiology at the Charité-Universitätsmedizin Berlin. We also thank Sarah Moreno Garcia for DNA preparation and Biobank management. Stefan Mundlos provided additional expertise for genetic analyses within the BIH-Charité Junior Clinician Scientist Program. Maria Heinrich is participant in the BIH-Charité Digital Clinician Scientist Program funded by the Charité –Universitätsmedizin Berlin and the Berlin Institute of Health. This program was initiated and led by Prof. Dr. Duska Dragun to enable resident physicians to pursue a career in digital health and academic research. With great sadness we have received the news that Prof. Dragun passed away on December 28th of 2020. This publication is dedicated to her as a mentor, role model and stellar scientist.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10/21
Y1 - 2021/10/21
N2 - BACKGROUND: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are frequent and serious complications after surgery. We aim to investigate the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes - pathway: cholinergic neurotransmission with the development of POD or POCD in elderly patients.METHODS: This analysis is part of the European BioCog project ( www.biocog.eu ), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental-State-Examination score ≤ 23 points were excluded. POD was assessed up to seven days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. POCD was assessed three months after surgery with a neuropsychological test battery. Genotyping was performed on the Illumina Infinium Global Screening Array. Associations with POD and POCD were analyzed using logistic regression analysis, adjusted for age, comorbidities and duration of anesthesia (for POCD analysis additionally for education). Odds ratios (OR) refer to minor allele counts (0, 1, 2).RESULTS: 745 patients could be included in the POD analysis, and 452 in the POCD analysis. The rate of POD within this group was 20.8% (155 patients), and the rate of POCD was 10.2% (46 patients). In a candidate gene approach three genetic variants of the cholinergic genes CHRM2 and CHRM4 were associated with POD (OR [95% confidence interval], rs8191992: 0.61[0.46; 0.80]; rs8191992: 1.60[1.22; 2.09]; rs2067482: 1.64[1.10; 2.44]). No associations were found for POCD.CONCLUSIONS: We found an association between genetic variants of CHRM2 and CHRM4 and POD. Further studies are needed to investigate whether disturbances in acetylcholine release and synaptic plasticity are involved in the development of POD.TRIAL REGISTRATION: ClinicalTrials.gov: NCT02265263.
AB - BACKGROUND: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are frequent and serious complications after surgery. We aim to investigate the association between genetic variants in cholinergic candidate genes according to the Kyoto encyclopedia of genes and genomes - pathway: cholinergic neurotransmission with the development of POD or POCD in elderly patients.METHODS: This analysis is part of the European BioCog project ( www.biocog.eu ), a prospective multicenter observational study with elderly surgical patients. Patients with a Mini-Mental-State-Examination score ≤ 23 points were excluded. POD was assessed up to seven days after surgery using the Nursing Delirium Screening Scale, Confusion Assessment Method and a patient chart review. POCD was assessed three months after surgery with a neuropsychological test battery. Genotyping was performed on the Illumina Infinium Global Screening Array. Associations with POD and POCD were analyzed using logistic regression analysis, adjusted for age, comorbidities and duration of anesthesia (for POCD analysis additionally for education). Odds ratios (OR) refer to minor allele counts (0, 1, 2).RESULTS: 745 patients could be included in the POD analysis, and 452 in the POCD analysis. The rate of POD within this group was 20.8% (155 patients), and the rate of POCD was 10.2% (46 patients). In a candidate gene approach three genetic variants of the cholinergic genes CHRM2 and CHRM4 were associated with POD (OR [95% confidence interval], rs8191992: 0.61[0.46; 0.80]; rs8191992: 1.60[1.22; 2.09]; rs2067482: 1.64[1.10; 2.44]). No associations were found for POCD.CONCLUSIONS: We found an association between genetic variants of CHRM2 and CHRM4 and POD. Further studies are needed to investigate whether disturbances in acetylcholine release and synaptic plasticity are involved in the development of POD.TRIAL REGISTRATION: ClinicalTrials.gov: NCT02265263.
KW - CHRM2
KW - CHRM4
KW - Genome-wide association study
KW - Neurocognitive disorder
UR - http://www.scopus.com/inward/record.url?scp=85117685941&partnerID=8YFLogxK
U2 - 10.1186/s12920-021-01071-1
DO - 10.1186/s12920-021-01071-1
M3 - Article
C2 - 34674705
SN - 1755-8794
VL - 14
SP - 1
EP - 10
JO - BMC Medical Genomics [E]
JF - BMC Medical Genomics [E]
IS - 1
M1 - 248
ER -