Team Hamsten

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Research focus

Molecular pathophysiology of coronary artery disease

Introduction

The overarching objective of the Hamsten team is to understand the causes and mechanisms operating in coronary artery disease (CAD), to create novel tools for CAD risk assessment and pave the way for novel treatment strategies.

Research in the team lead by Professor Anders Hamsten is performed by four integrated working groups with support of a technical platform for biostatistics, assays and biobanks.

Susceptibility genes and quantitative traits - Biomarkers

The genetics of atherothrombotic disease, such as coronary artery disease (CAD) remains enigmatic, despite the 46 robustly associated CAD loci identified so far through collaborative efforts in which we have been active. We pursue two complementary approaches, investigation of directly disease-related genetic associations and Quantitative Traits Locus (QTL) studies of intermediate phenotypes. The latter include biochemical markers related to atherothrombotic, inflammatory or metabolic pathways, but also vascular imaging of sub-clinical atherosclerosis. Distinguishing the processes which actively contribute to disease progression from those which result from pathogenic processes is a key aim. The human clinical material comprises well-characterised cohorts, both Swedish and international, collected through in-house efforts or in collaborative consortia. SNP data are obtained from genome-wide and bespoke genotyping arrays, and 1000 Genome imputations. We have dedicated bioinformatics and biostatistics expertise that ensure the adaptation of statistical methods to challenges imposed by new high throughput data generation; this includes substantial in-house method development. In addition to in-house research, the working group is also active participant in international genetics consortia including PROCARDIS, IMPROVE, CARDIOGRAMplusC4D , CHARGE, GIANT, MAGIC, DIAGRAM, ICBP and GlobalLipids.

Atherosclerosis-related cardiovascular disease (CVD) such as coronary artery disease (CAD) begins to develop long before any symptoms appear. The early stage of CVD is characterized by development of sub-clinical atherosclerosis under the influence of risk factors. Thus, there is a window of opportunity to identify high-risk individuals. There is however need for novel biomarkers beyond those represented by currently established risk factors, for efficient identification of risk individuals and monitoring of disease progression in a sensitive and specific manner. Distinguishing the processes which actively contribute to disease progression from those which are consequences thereof is a key in order to understand disease mechanisms and to uncover new potential targets for therapeutics. We look at biochemical markers related to atherothrombotic, inflammatory and metabolic pathways, as well as vascular imaging of atherosclerosis. We are exploring new high throughput genomics, lipidomics and proteomics methodologies to discover new molecules and pathways involved in CVD, in collaboration with researchers at SciLifeLab and Department of Medical Biochemistry and Biophysics at KI and international consortia such as CHARGE, IMPROVE, and SUMMIT. We also use genetic information to establish causal risk factors by means of Mendelian randomization approaches.

Participants 

Contact: Angela Silveira, Associate Professor, PhD, biochemist, plasma biomarkers

Rona Strawbridge, PhD, Research Assistant Professor (FoAss), Biochemist, Genetics of obesity, gluco-metabolic and cardiovascular traits

Anders Mälarstig, PhD,

Maria Sabater Lleal, PhD, Research Assistant Professor, Genetics of cardiovascular disease

Functional characterization of genes and gene variants

The area of interest of this team is on the identification and functional characterization of novel genes, pathways and proteins involved in lipid and lipoprotein metabolism. Our research focus is on the genetic and metabolic analysis of genes in human liver, using gene expression data from human liver samples and cell-biological studies in the Huh7 and HepG2 hepatoma cell-lines. For the identification of novel genes we explore genetic loci identified by GWAS using fine-mapping methods and eQTL analysis of the human liver samples. The functional characterization of genes in cell-culture models are mainly directed towards genes involved in hepatic triglyceride metabolism, with special emphasis on genes with metabolic roles in hepatic steatosis and/or the secretion of triglyceride-rich lipoproteins. 

Participants

Contact: Ferdinand van’t Hooft, MD, PhD, senior scientist, functional genetics

Maria Nastase Mannila, MD, PhD, cardiology and internal medicine, cardiogenetics

Apostolos Taxiarchis, PhD student, molecular biologist, cell-biological studies

Networks and collaborations

Anders Hamsten is a founding member and PI of the PROCARDIS, a European Concerted Action on the genome-wide search for genes implicated in CAD. The programme, which was initiated in October 1998, now includes 8 academic units and 3 industrial partners and has attracted substantial financial support from the European Commission (FP5 and FP6) and the Knut and Alice Wallenberg Foundation. The team is also a partner in the Leducq Network of Excellence in Atherothrombosis (LENA) and has an active role in the MAGIC, CHARGE, GIANT and GlobalBPGen consortia, the latter four networks addressing the genetic regulation of glucometabolic (MAGIC), haemostatic (CHARGE), anthropometric (GIANT) and blood pressure (Global BP Gen) traits. Within KI, Anders Hamsten is a PI in the Center for Research on Inflammation and Cardiovascular Disease (CERIC), supported by the Swedish Research Council.

Team members

Fariba Foroogh, BSc, Research Engineer

Anders Hamsten, MD, PhD, Professor, Team Leader

Ferdinand van't Hooft, MD, PhD, Senior Researcher

Anders Mälarstig, PhD (Associated)

Maria Nastase Mannila, MD, PhD, Post Doctoral Fellow

Maria Sabater Lleal, PhD, Post Doctoral Fellow

Angela Silveira, PhD, Associate Professor, Senior Researcher

Rona Strawbridge, PhD, Post Doctoral Fellow

Apostolos Taxiarchis,  PhD student, molecular biologist, cell-biological studies

Publications

Large-scale association analysis identifies new risk loci for coronary artery disease.
, Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes T, et al
Nat. Genet. 2013 Jan;45(1):25-33

Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.
Sabater-Lleal M, Huang J, Chasman D, Naitza S, Dehghan A, Johnson A, et al
Circulation 2013 Sep;128(12):1310-24

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.
Huang J, Sabater-Lleal M, Asselbergs F, Tregouet D, Shin S, Ding J, et al
Blood 2012 Dec;120(24):4873-81

Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.
Gertow K, Sennblad B, Strawbridge R, Ohrvik J, Zabaneh D, Shah S, et al
Circ Cardiovasc Genet 2012 Dec;5(6):656-65

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.
Strawbridge R, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, et al
Diabetes 2011 Oct;60(10):2624-34

A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease.

Nat. Genet. 2011 Mar;43(4):339-44

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.
Morris A, Voight B, Teslovich T, Ferreira T, Segrè A, Steinthorsdottir V, et al
Nat. Genet. 2012 Sep;44(9):981-90

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.
Scott R, Lagou V, Welch R, Wheeler E, Montasser M, Luan J, et al
Nat. Genet. 2012 Sep;44(9):991-1005

A genome-wide association study identifies KNG1 as a genetic determinant of plasma factor XI Level and activated partial thromboplastin time.
Sabater-Lleal M, Martinez-Perez A, Buil A, Folkersen L, Souto J, Bruzelius M, et al
Arterioscler. Thromb. Vasc. Biol. 2012 Aug;32(8):2008-16

Large-scale gene-centric analysis identifies novel variants for coronary artery disease.

PLoS Genet. 2011 Sep;7(9):e1002260

Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study.
Holmes M, Simon T, Exeter H, Folkersen L, Asselbergs F, Guardiola M, et al
J. Am. Coll. Cardiol. 2013 Nov;62(21):1966-1976

The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.
, Swerdlow D, Holmes M, Kuchenbaecker K, Engmann J, Shah T, et al
Lancet 2012 Mar;379(9822):1214-24

Causal relevance of blood lipid fractions in the development of carotid atherosclerosis: Mendelian randomization analysis.
Shah S, Casas J, Drenos F, Whittaker J, Deanfield J, Swerdlow D, et al
Circ Cardiovasc Genet 2013 Feb;6(1):63-72

Serum 25-hydroxyvitamin D concentration in subclinical carotid atherosclerosis.
Deleskog A, Piksasova O, Silveira A, Gertow K, Baldassarre D, Veglia F, et al
Arterioscler. Thromb. Vasc. Biol. 2013 Nov;33(11):2633-8

Serum 25-hydroxyvitamin D concentration, established and emerging cardiovascular risk factors and risk of myocardial infarction before the age of 60 years.
Deleskog A, Piksasova O, Silveira A, Samnegård A, Tornvall P, Eriksson P, et al
Atherosclerosis 2012 Jul;223(1):223-9

Progression of carotid intima-media thickness as predictor of vascular events: results from the IMPROVE study.
Baldassarre D, Veglia F, Hamsten A, Humphries S, Rauramaa R, de Faire U, et al
Arterioscler. Thromb. Vasc. Biol. 2013 Sep;33(9):2273-9

A genome-wide association study identifies KNG1 as a genetic determinant of plasma factor XI Level and activated partial thromboplastin time.
Sabater-Lleal M, Martinez-Perez A, Buil A, Folkersen L, Souto J, Bruzelius M, et al
Arterioscler. Thromb. Vasc. Biol. 2012 Aug;32(8):2008-16

Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.
Gertow K, Sennblad B, Strawbridge R, Ohrvik J, Zabaneh D, Shah S, et al
Circ Cardiovasc Genet 2012 Dec;5(6):656-65

Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study.
Baldassarre D, Nyyssönen K, Rauramaa R, de Faire U, Hamsten A, Smit A, et al
Eur. Heart J. 2010 Mar;31(5):614-22

Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.
Huang J, Sabater-Lleal M, Asselbergs F, Tregouet D, Shin S, Ding J, et al
Blood 2012 Dec;120(24):4873-81

Relationships of plasma factor VIIa-antithrombin complexes to manifest and future cardiovascular disease.
Silveira A, Scanavini D, Boquist S, Ericsson C, Hellénius M, Leander K, et al
Thromb. Res. 2012 Aug;130(2):221-5

Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study.
Baldassarre D, Hamsten A, Veglia F, de Faire U, Humphries S, Smit A, et al
J. Am. Coll. Cardiol. 2012 Oct;60(16):1489-99

Plasma CD93 concentration is a potential novel biomarker for coronary artery disease.
Mälarstig A, Silveira A, Wågsäter D, Öhrvik J, Bäcklund A, Samnegård A, et al
J. Intern. Med. 2011 Sep;270(3):229-36

DGAT1 participates in the effect of HNF4A on hepatic secretion of triglyceride-rich lipoproteins.
Krapivner S, Iglesias M, Silveira A, Tegnér J, Björkegren J, Hamsten A, et al
Arterioscler. Thromb. Vasc. Biol. 2010 May;30(5):962-7

Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease.
Folkersen L, van't Hooft F, Chernogubova E, Agardh H, Hansson G, Hedin U, et al
Circ Cardiovasc Genet 2010 Aug;3(4):365-73

Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels.
Chernogubova E, Strawbridge R, Mahdessian H, Mälarstig A, Krapivner S, Gigante B, et al
Arterioscler. Thromb. Vasc. Biol. 2012 Jun;32(6):1526-34

Identification of a functional apolipoprotein E promoter polymorphism regulating plasma apolipoprotein E concentration.
Mannila M, Mahdessian H, Franco-Cereceda A, Eggertsen G, de Faire U, Syvänen A, et al
Arterioscler. Thromb. Vasc. Biol. 2013 May;33(5):1063-9