ORCID Profile
0000-0003-1945-7425
Current Organisations
Karolinska University Hospital
,
Stockholm University
,
University of Tartu
,
Karolinska Institutet
,
Gladstone Institute of Cardiovascular Disease
,
Icahn School of Medicine at Mount Sinai
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Publications
Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
Publisher: Springer Science and Business Media LLC
Date: 12-03-2018
Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-01-2017
DOI: 10.1161/CIRCRESAHA.116.308765
Abstract: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. To identify additional AAA risk loci using data from all available genome-wide association studies. Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 ( SMYD2 ), 13q12.11 ( LINC00540 ), 20q13.12 (near PCIF1 / MMP9 / ZNF335 ), and 21q22.2 ( ERG ). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG , IL6R , and LDLR as modifiers of MMP9 , with a direct interaction between ERG and MMP9 . The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
Systems biology of innate immunity
Publisher: Elsevier BV
Date: 12-2006
Transcriptional network dynamics in macrophage activation
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.YGENO.2006.03.022
Abstract: Transcriptional regulatory networks govern cell differentiation and the cellular response to external stimuli. However, mammalian model systems have not yet been accessible for network analysis. Here, we present a genome-wide network analysis of the transcriptional regulation underlying the mouse macrophage response to bacterial lipopolysaccharide (LPS). Key to uncovering the network structure is our combination of time-series cap analysis of gene expression with in silico prediction of transcription factor binding sites. By integrating microarray and qPCR time-series expression data with a promoter analysis, we find dynamic subnetworks that describe how signaling pathways change dynamically during the progress of the macrophage LPS response, thus defining regulatory modules characteristic of the inflammatory response. In particular, our integrative analysis enabled us to suggest novel roles for the transcription factors ATF-3 and NRF-2 during the inflammatory response. We believe that our system approach presented here is applicable to understanding cellular differentiation in higher eukaryotes.
Genome-wide analysis identifies novel susceptibility loci for myocardial infarction
Publisher: Oxford University Press (OUP)
Date: 03-02-2021
DOI: 10.1093/EURHEARTJ/EHAA1040
Abstract: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro. A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
Integrative Prioritization of Causal Genes for Coronary Artery Disease
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2022
DOI: 10.1161/CIRCGEN.121.003365
Abstract: Hundreds of candidate genes have been associated with coronary artery disease (CAD) through genome-wide association studies. However, a systematic way to understand the causal mechanism(s) of these genes, and a means to prioritize them for further study, has been lacking. This represents a major roadblock for developing novel disease- and gene-specific therapies for patients with CAD. Recently, powerful integrative genomics analyses pipelines have emerged to identify and prioritize candidate causal genes by integrating tissue/cell-specific gene expression data with genome-wide association study data sets. We aimed to develop a comprehensive integrative genomics analyses pipeline for CAD and to provide a prioritized list of causal CAD genes. To this end, we leveraged several complimentary informatics approaches to integrate summary statistics from CAD genome-wide association studies (from UK Biobank and CARDIoGRAMplusC4D) with transcriptomic and expression quantitative trait loci data from 9 cardiometabolic tissue/cell types in the STARNET study (Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task). We identified 162 unique candidate causal CAD genes, which exerted their effect from between one and up to 7 disease-relevant tissues/cell types, including the arterial wall, blood, liver, skeletal muscle, adipose, foam cells, and macrophages. When their causal effect was ranked, the top candidate causal CAD genes were CDKN2B (associated with the 9p21.3 risk locus) and PHACTR1 both exerting their causal effect in the arterial wall. A majority of candidate causal genes were represented in cross-tissue gene regulatory co-expression networks that are involved with CAD, with 22/162 being key drivers in those networks. We identified and prioritized candidate causal CAD genes, also localizing their tissue(s) of causal effect. These results should serve as a resource and facilitate targeted studies to identify the functional impact of top causal CAD genes.
Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes
Publisher: Springer Science and Business Media LLC
Date: 03-06-2019
DOI: 10.1038/S41588-019-0449-0
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Publisher: Springer Science and Business Media LLC
Date: 03-12-2018
DOI: 10.1038/S41467-018-07340-5
Abstract: 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 in iduals for cIMT, and 48,434 in iduals 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.
Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity
Publisher: Springer Science and Business Media LLC
Date: 06-09-2017
DOI: 10.1038/S41598-017-10410-1
Abstract: Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH- dependent production of 20β-dihydrocortisol (20β-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20β-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20β-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.
Related Organisations
Gladstone Institute Of Cardiovascular Disease
Location: United States of America
Icahn School Of Medicine At Mount Sinai
Location: United States of America
Related Funding Activities
No related grants have been discovered for Johan Björkegren.