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Team Hamsten

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

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

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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

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