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Article ; Online: Associations of ABO and Rhesus D blood groups with phenome-wide disease incidence

Peter Bruun-Rasmussen / Morten Hanefeld Dziegiel / Karina Banasik / Pär Ingemar Johansson / Søren Brunak

eLife, Vol

A 41-year retrospective cohort study of 482,914 patients

2023 Volume 12

Abstract: Background: Whether natural selection may have attributed to the observed blood group frequency differences between populations remains debatable. The ABO system has been associated with several diseases and recently also with susceptibility to COVID-19 ... ...

Abstract	Background: Whether natural selection may have attributed to the observed blood group frequency differences between populations remains debatable. The ABO system has been associated with several diseases and recently also with susceptibility to COVID-19 infection. Associative studies of the RhD system and diseases are sparser. A large disease-wide risk analysis may further elucidate the relationship between the ABO/RhD blood groups and disease incidence. Methods: We performed a systematic log-linear quasi-Poisson regression analysis of the ABO/RhD blood groups across 1,312 phecode diagnoses. Unlike prior studies, we determined the incidence rate ratio for each individual ABO blood group relative to all other ABO blood groups as opposed to using blood group O as the reference. Moreover, we used up to 41 years of nationwide Danish follow-up data, and a disease categorization scheme specifically developed for diagnosis-wide analysis. Further, we determined associations between the ABO/RhD blood groups and the age at the first diagnosis. Estimates were adjusted for multiple testing. Results: The retrospective cohort included 482,914 Danish patients (60.4% females). The incidence rate ratios (IRRs) of 101 phecodes were found statistically significant between the ABO blood groups, while the IRRs of 28 phecodes were found statistically significant for the RhD blood group. The associations included cancers and musculoskeletal-, genitourinary-, endocrinal-, infectious-, cardiovascular-, and gastrointestinal diseases. Conclusions: We found associations of disease-wide susceptibility differences between the blood groups of the ABO and RhD systems, including cancer of the tongue, monocytic leukemia, cervical cancer, osteoarthrosis, asthma, and HIV- and hepatitis B infection. We found marginal evidence of associations between the blood groups and the age at first diagnosis. Funding: Novo Nordisk Foundation and the Innovation Fund Denmark
Keywords	ABO blood groups ; RhD blood groups ; phewas ; disease-wide associations ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Associations of ABO and Rhesus D blood groups with phenome-wide disease incidence: A 41-year retrospective cohort study of 482,914 patients.

Bruun-Rasmussen, Peter / Hanefeld Dziegiel, Morten / Banasik, Karina / Johansson, Pär Ingemar / Brunak, Søren

eLife

2023 Volume 12

Abstract	Background: Whether natural selection may have attributed to the observed blood group frequency differences between populations remains debatable. The ABO system has been associated with several diseases and recently also with susceptibility to COVID-19 infection. Associative studies of the RhD system and diseases are sparser. A large disease-wide risk analysis may further elucidate the relationship between the ABO/RhD blood groups and disease incidence. Methods: We performed a systematic log-linear quasi-Poisson regression analysis of the ABO/RhD blood groups across 1,312 phecode diagnoses. Unlike prior studies, we determined the incidence rate ratio for each individual ABO blood group relative to all other ABO blood groups as opposed to using blood group O as the reference. Moreover, we used up to 41 years of nationwide Danish follow-up data, and a disease categorization scheme specifically developed for diagnosis-wide analysis. Further, we determined associations between the ABO/RhD blood groups and the age at the first diagnosis. Estimates were adjusted for multiple testing. Results: The retrospective cohort included 482,914 Danish patients (60.4% females). The incidence rate ratios (IRRs) of 101 phecodes were found statistically significant between the ABO blood groups, while the IRRs of 28 phecodes were found statistically significant for the RhD blood group. The associations included cancers and musculoskeletal-, genitourinary-, endocrinal-, infectious-, cardiovascular-, and gastrointestinal diseases. Conclusions: We found associations of disease-wide susceptibility differences between the blood groups of the ABO and RhD systems, including cancer of the tongue, monocytic leukemia, cervical cancer, osteoarthrosis, asthma, and HIV- and hepatitis B infection. We found marginal evidence of associations between the blood groups and the age at first diagnosis. Funding: Novo Nordisk Foundation and the Innovation Fund Denmark.
MeSH term(s)	Female ; Male ; Humans ; ABO Blood-Group System/genetics ; Retrospective Studies ; COVID-19 ; Rh-Hr Blood-Group System/genetics ; Risk Assessment ; Disease Susceptibility ; Neoplasms
Chemical Substances	ABO Blood-Group System ; Rh-Hr Blood-Group System
Language	English
Publishing date	2023-03-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.83116
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Article ; Online: The Effect of Targeted Temperature Management on the Metabolome Following Out-of-Hospital Cardiac Arrest.

Beske, Rasmus Paulin / Obling, Laust Emil Roelsgaard / Bro-Jeppesen, John / Nielsen, Niklas / Meyer, Martin Abild Steengaard / Kjaergaard, Jesper / Johansson, Pär Ingemar / Hassager, Christian

Therapeutic hypothermia and temperature management

2023 Volume 13, Issue 4, Page(s) 208–215

Abstract: Targeted temperature management (TTM) may moderate the injury from out-of-hospital cardiac arrest. Slowing the metabolism has been a suggested effect. Nevertheless, studies have found higher lactate levels in patients cooled to 33°C compared with 36°C ... ...

Abstract	Targeted temperature management (TTM) may moderate the injury from out-of-hospital cardiac arrest. Slowing the metabolism has been a suggested effect. Nevertheless, studies have found higher lactate levels in patients cooled to 33°C compared with 36°C even days from TTM cessation. Larger studies have not been performed on the TTM's effect on the metabolome. Accordingly, to explore the effect of TTM, we used ultra-performance liquid-mass spectrometry in a substudy of 146 patients randomized in the TTM trial to either 33°C or 36°C for 24 hours and quantified 60 circulating metabolites at the time of hospital arrival (T
MeSH term(s)	Humans ; Hypothermia, Induced/methods ; Out-of-Hospital Cardiac Arrest/therapy ; Cold Temperature ; Metabolome ; Amino Acids ; Cardiopulmonary Resuscitation/methods
Chemical Substances	Amino Acids
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	2609342-X
ISSN	2153-7933 ; 2153-7658
ISSN (online)	2153-7933
ISSN	2153-7658
DOI	10.1089/ther.2022.0065
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Article ; Online: Estimating the effect of donor sex on red blood cell transfused patient mortality: A retrospective cohort study using a targeted learning and emulated trials-based approach.

Bruun-Rasmussen, Peter / Andersen, Per Kragh / Banasik, Karina / Brunak, Søren / Johansson, Pär Ingemar

EClinicalMedicine

2022 Volume 51, Page(s) 101628

Abstract: Background: Observational studies determining the effect of red blood cell (RBC) donor sex on recipient mortality have been inconsistent. Emulating hypothetical randomized target trials using large real-world data and targeted learning may clarify ... ...

Abstract	Background: Observational studies determining the effect of red blood cell (RBC) donor sex on recipient mortality have been inconsistent. Emulating hypothetical randomized target trials using large real-world data and targeted learning may clarify potential adverse effects. Methods: In this retrospective cohort study, a RBC transfusion database from the Capital Region of Denmark comprising more than 900,000 transfusion events defined the observational data. Eligible patients were minimum 18 years, had received a leukocyte-reduced RBC transfusion, and had no history of RBC transfusions within the past year at baseline. The doubly robust targeted maximum likelihood estimation method coupled with ensembled machine learning was used to emulate sex-stratified target trials determining the comparative effectiveness of exclusively transfusing RBC units from either male or female donors. The outcome was all-cause mortality within 28 days of the baseline-transfusion. Estimates were adjusted for the total number of transfusions received on each day Findings: Among 98,167 adult patients who were transfused between Jan. 1, 2008, and Apr. 10, 2018, a total of 90,917 patients (54.6% female) were eligible. For male patients, the 28-day survival was 2.06 percentage points (pp) (95 % confidence interval [CI]: 1.81-2.32, Interpretation: The results suggest that a sex-matched transfusion policy may benefit patients. However, a causal interpretation of the findings relies on the assumption of no unmeasured confounding, treatment consistency, positivity, and minimal model misspecifications. Funding: Novo Nordisk Foundation and the Innovation Fund Denmark.
Language	English
Publishing date	2022-08-27
Publishing country	England
Document type	Journal Article
ISSN	2589-5370
ISSN (online)	2589-5370
DOI	10.1016/j.eclinm.2022.101628
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Article ; Online: Intervening on the storage time of RBC units and its effects on adverse recipient outcomes using real-world data.

Bruun-Rasmussen, Peter / Kragh Andersen, Per / Banasik, Karina / Brunak, Søren / Johansson, Pär Ingemar

Blood

2022 Volume 139, Issue 25, Page(s) 3647–3654

Abstract: Randomized controlled trials (RCTs) have found no evidence that the storage time of transfused red blood cell (RBC) units affects recipient survival. However, inherent difficulties in conducting RBC transfusion RCTs have prompted critique of their design, ...

Abstract	Randomized controlled trials (RCTs) have found no evidence that the storage time of transfused red blood cell (RBC) units affects recipient survival. However, inherent difficulties in conducting RBC transfusion RCTs have prompted critique of their design, analyses, and interpretation. Here, we address these issues by emulating hypothetical randomized trials using large real-world data to further clarify the adverse effects of storage time. We estimated the comparative effect of transfusing exclusively older vs fresher RBC units on the primary outcome of death, and the secondary composite end point of thromboembolic events, or death, using inverse probability weighting. Thresholds were defined as 1, 2, 3, and 4 weeks of storage. A large Danish blood transfusion database from the period 2008 to 2018 comprising >900 000 transfusion events defined the observational data. A total of 89 799 patients receiving >340 000 RBC transfusions during 28 days of follow-up met the eligibility criteria. Treatment with RBC units exclusively fresher than 1, 2, 3, and 4 weeks of storage was found to decrease the 28-day recipient mortality with 2.44 percentage points (pp) (0.86 pp, 4.02 pp), 1.93 pp (0.85 pp, 3.02 pp), 1.06 pp (-0.20 pp, 2.33 pp), and -0.26 pp (-1.78 pp, 1.25 pp) compared with transfusing exclusively older RBC units, respectively. The 28-day risk differences for the composite end point were similar. This study suggests that transfusing exclusively older RBC units stored for >1 or 2 weeks increases the 28-day recipient mortality and risk of thromboembolism or death compared with transfusing fresher RBC units.
MeSH term(s)	Blood Preservation ; Erythrocyte Transfusion/adverse effects ; Humans
Language	English
Publishing date	2022-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022015892
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Article ; Online: Major open abdominal surgery is associated with increased levels of endothelial damage and interleukin-6.

Gregersen, Jeppe Skovgaard / Bazancir, Laser Arif / Johansson, Pär Ingemar / Sørensen, Henrik / Achiam, Michael Patrick / Olsen, August Adelsten

Microvascular research

2023 Volume 148, Page(s) 104543

Abstract: Objective: To examine changes in biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress following major open abdominal surgery and the correlation to postoperative morbidity.: Introduction: Major abdominal surgery is ... ...

Abstract	Objective: To examine changes in biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress following major open abdominal surgery and the correlation to postoperative morbidity. Introduction: Major abdominal surgery is associated with high levels of postoperative morbidity. Two possible reasons are the surgical stress response and the impairment of the glycocalyx and endothelial cells. Further, the degree of these responses may correlate with postoperative morbidity and complications. Methods: A secondary data analysis of prospectively collected data from two cohorts of patients undergoing open liver surgery, gastrectomy, esophagectomy, or Whipple procedure (n = 112). Hemodynamics and blood samples were collected at predefined timestamps and analyzed for biomarkers of glycocalyx shedding (Syndecan-1), endothelial activation (sVEGFR1), endothelial damage (sThrombomodulin (sTM)), and surgical stress (IL6). Results: Major abdominal surgery led to increased levels of IL6 (0 to 85 pg/mL), Syndecan-1 (17.2 to 46.4 ng/mL), and sVEGFR1 (382.8 to 526.5 pg/mL), peaking at the end of the surgery. In contrast, sTM, did not increase during surgery, but increased significantly following surgery (5.9 to 6.9 ng/mL), peaking at 18 h following the end of surgery. Patients characterized with high postoperative morbidity had higher levels of IL6 (132 vs. 78 pg/mL, p = 0.007) and sVEGFR1 (563.1 vs. 509.4 pg/mL, p = 0.045) at the end of the surgery, and of sTM (8.2 vs. 6.4 ng/mL, p = 0.038) 18 h following surgery. Conclusion: Major abdominal surgery leads to significantly increased levels of biomarkers of endothelial glycocalyx shedding, endothelial damage, and surgical stress, with the highest levels seen in patients developing high postoperative morbidity.
MeSH term(s)	Humans ; Interleukin-6 ; Endothelial Cells ; Syndecan-1 ; Endothelium ; Biomarkers ; Glycocalyx
Chemical Substances	Interleukin-6 ; Syndecan-1 ; Biomarkers
Language	English
Publishing date	2023-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80307-8
ISSN	1095-9319 ; 0026-2862
ISSN (online)	1095-9319
ISSN	0026-2862
DOI	10.1016/j.mvr.2023.104543
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Article ; Online: Erratum to: Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism.

Johansson, Pär Ingemar / Stensballe, Jakob / Ostrowski, Sisse Rye

Critical care (London, England)

2017 Volume 21, Issue 1, Page(s) 187

Language	English
Publishing date	2017-07-13
Publishing country	England
Document type	Published Erratum
ZDB-ID	2051256-9
ISSN	1466-609X ; 1466-609X
ISSN (online)	1466-609X
ISSN	1466-609X
DOI	10.1186/s13054-017-1756-4
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Article ; Online: Evaluation of the systemic inflammatory response, endothelial cell dysfunction, and postoperative morbidity in patients, receiving perioperative corticosteroid, developing severe mesenteric traction syndrome - an exploratory study.

Olsen, August Adelsten / Strandby, Rune Broni / Johansson, Pär Ingemar / Sørensen, Henrik / Svendsen, Lars Bo / Achiam, Michael Patrick

Langenbeck's archives of surgery

2022 Volume 407, Issue 5, Page(s) 2095–2103

Abstract: Objective: To determine whether a severe mesenteric traction syndrome (MTS) leads to increased surgical stress, endothelial dysfunction, and postoperative morbidity in a cohort in which all patients received a single dose of methylprednisolone.: ... ...

Abstract	Objective: To determine whether a severe mesenteric traction syndrome (MTS) leads to increased surgical stress, endothelial dysfunction, and postoperative morbidity in a cohort in which all patients received a single dose of methylprednisolone. Introduction: Preoperatively administered corticosteroids lower the incidence of severe MTS and may also attenuate surgical stress and endothelial damage associated with the development of severe MTS, ultimately lowering the postoperative morbidity. Methods: This exploratory study analyzed prospectively collected data from 45 patients all receiving 125 mg methylprednisolone. No control group was included. The severity of MTS was graded intraoperatively, and postoperative morbidity was assessed blinded. Blood samples for plasma prostacyclin (PGI Results: Patients undergoing either open liver surgery (n = 23) or Whipple's procedure (n = 22) were included. No differences were found in postoperative morbidity between patients developing and not developing severe MTS. Surgery led to significantly increased plasma levels of biomarkers indicative of surgical stress and endothelial damage. Further, patients developing severe MTS had increased levels of PGI Conclusion: This exploratory study found that surgery was associated with a pro-inflammatory response and damage to the endothelium. However, no differences were found between patients developing severe MTS and patients developing moderate/no MTS in biomarkers of surgical stress, endothelial damage, or postoperative morbidity. Corticosteroids may therefore attenuate the endothelial damage in patients developing severe MTS. However, as this was an exploratory study, these findings must be confirmed in future randomized controlled studies.
MeSH term(s)	Adrenal Cortex Hormones ; Biomarkers ; Endothelial Cells ; Humans ; Methylprednisolone/therapeutic use ; Morbidity ; Syndrome ; Systemic Inflammatory Response Syndrome/prevention & control ; Traction
Chemical Substances	Adrenal Cortex Hormones ; Biomarkers ; Methylprednisolone (X4W7ZR7023)
Language	English
Publishing date	2022-04-09
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1423681-3
ISSN	1435-2451 ; 1435-2443
ISSN (online)	1435-2451
ISSN	1435-2443
DOI	10.1007/s00423-022-02507-7
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Article ; Online: Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism.

Johansson, Pär Ingemar / Stensballe, Jakob / Ostrowski, Sisse Rye

Critical care (London, England)

2017 Volume 21, Issue 1, Page(s) 25

Abstract: One quarter of patients suffering from acute critical illness such as severe trauma, sepsis, myocardial infarction (MI) or post cardiac arrest syndrome (PCAS) develop severe hemostatic aberrations and coagulopathy, which are associated with excess ... ...

Abstract	One quarter of patients suffering from acute critical illness such as severe trauma, sepsis, myocardial infarction (MI) or post cardiac arrest syndrome (PCAS) develop severe hemostatic aberrations and coagulopathy, which are associated with excess mortality. Despite the different types of injurious "hit", acutely critically ill patients share several phenotypic features that may be driven by the shock. This response, mounted by the body to various life-threatening conditions, is relatively homogenous and most likely evolutionarily adapted. We propose that shock-induced sympatho-adrenal hyperactivation is a critical driver of endothelial cell and glycocalyx damage (endotheliopathy) in acute critical illness, with the overall aim of ensuring organ perfusion through an injured microvasculature. We have investigated more than 3000 patients suffering from different types of acute critical illness (severe trauma, sepsis, MI and PCAS) and have found a potential unifying pathologic link between sympatho-adrenal hyperactivation, endotheliopathy, and poor outcome. We entitled this proposed disease entity, shock-induced endotheliopathy (SHINE). Here we review the literature and discuss the pathophysiology of SHINE.
MeSH term(s)	Blood Coagulation Disorders/etiology ; Blood Coagulation Disorders/physiopathology ; Critical Illness/mortality ; Endothelium/injuries ; Endothelium/physiopathology ; Hemostasis/physiology ; Humans ; Injury Severity Score ; Shock/complications ; Shock/physiopathology
Language	English
Publishing date	2017-02-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2051256-9
ISSN	1466-609X ; 1466-609X
ISSN (online)	1466-609X
ISSN	1466-609X
DOI	10.1186/s13054-017-1605-5
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Article ; Online: Severe mesenteric traction syndrome is associated with increased systemic inflammatory response, endothelial dysfunction, and major postoperative morbidity.

Olsen, August Adelsten / Strandby, Rune Broni / Nerup, Nikolaj / Johansson, Pär Ingemar / Svendsen, Lars Bo / Achiam, Michael Patrick

Langenbeck's archives of surgery

2021 Volume 406, Issue 7, Page(s) 2457–2467

Abstract: This study aimed to determine if mesenteric traction syndrome (MTS) triggers increased systemic inflammation and endothelial cell dysfunction. Patients developing severe MTS had pronounced early IL6 elevations followed by endothelial cell damage. ... ...

Abstract	This study aimed to determine if mesenteric traction syndrome (MTS) triggers increased systemic inflammation and endothelial cell dysfunction. Patients developing severe MTS had pronounced early IL6 elevations followed by endothelial cell damage. Furthermore, these processes were associated with increased postoperative morbidity. Objective: To determine whether mesenteric traction syndrome (MTS) leads to increased systemic inflammation and dysfunction of the glycocalyx and endothelial cell and whether this correlates with the degree of postoperative morbidity. Introduction: Severe MTS is associated with increased postoperative morbidity following major gastrointestinal surgery, but the pathophysiological mechanism has not been previously explored. Systemic inflammatory response and impaired glycocalyx and endothelial cells may be responsible for the development of symptoms. Methods: The study analyzed prospectively collected data from two cohorts (n = 67). The severity of the MTS response was graded intraoperatively and blood samples for PGI Results: Patients undergoing either esophagectomy (n = 45) or gastrectomy (n = 22) were included. Surgery led to significantly increased plasma concentrations of all biomarkers. Yet, patients who developed severe MTS had higher baseline epinephrine levels (p < 0.05) and higher levels of PGI Conclusion: The development of severe MTS during upper gastrointestinal surgery is associated with preoperative elevated plasma epinephrine and further a more pronounced proinflammatory response and damage to the vascular endothelium. The increased postoperative morbidity seen in patients with severe MTS may thus, in part, be explained by an inherent susceptibility towards an inappropriate secretion of PGI
MeSH term(s)	Endothelial Cells/pathology ; Esophagectomy/adverse effects ; Gastrectomy/adverse effects ; Humans ; Morbidity ; Prospective Studies ; Systemic Inflammatory Response Syndrome/epidemiology ; Systemic Inflammatory Response Syndrome/etiology
Language	English
Publishing date	2021-03-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1423681-3
ISSN	1435-2451 ; 1435-2443
ISSN (online)	1435-2451
ISSN	1435-2443
DOI	10.1007/s00423-021-02111-1
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