Ongoing projects in Molecular epidemiology
Our research group has been taking a very active part in the various ongoing large-scale international genetics projects within the area of cardiovascular and metabolic disorders in the past five years. The work within these consortia has led to landmark papers dissecting the genetic architecture of complex traits within obesity, diabetes and cardiovascular disease. As a whole, these papers have not only identified hundreds of novel genetic loci associated with cardiovascular traits, but also dramatically increased the understanding of the genetic architecture of complex traits and the biology underlying these conditions.
Since 2010, we have also been working with Mendelian randomization (MR) as a method to address causality - a key concept in clinical medicine and epidemiology. Several of these international projects that Prof. Fall and Prof. Ingelsson have now been published in high-impact journals, and we have several additional projects using this methodology in the pipeline. We have also taken part in more methodological work in this field.
We have had a strong interest in studies of biomarkers measured in human biosamples in the past decade, and have been working extensively with prediction of cardiovascular disease by use of both traditional and more novel biomarkers and by use of different statistical metrics for prediction.
We have a range of ongoing projects using transcriptomics, epigenomics, proteomics, metabolomics, microbiomics - all aiming at increase the biological knowledge of cardiovascular diseases and to identify new biomarkers and drug targets. In proteomics, we are working with the proximity extension assay and have published several papers during 2015, one of them selected as one of the scientific highlights for SciLifeLab in 2015. In metabolomics, we are using liquid chromatography (LC)- and gas chromatography (GC-) tandem mass spectrometry (MS/MS) methods, and we have run analyses in about 5,500 samples from several longitudinal cohort studies and published several important papers on coronary heart disease and insulin resistance. Regarding microbiomics, we are currently analyzing 5,000 fecal samples from the SCAPIS cohort. Over the next few years, we plan to continue to analyse new samples using these methods, combine data across studies and data types, and to use -omics to improve knowledge about cardiometabolic diseases.
In 2018, Tove Fall was awarded an ERC Starting Grant on her large project on the influence of the gut microbiota on atherosclerosis and metabolism. Atherosclerosis is the main pathological mechanism causing myocardial infarction and ischemic stroke. Evidence has mounted about the association between the gut microbiota and cardiovascular disease, but whether the associations are causal is largely unknown. For optimal prevention and treatment of cardiovascular disease, there is an urgent need to determine whether there are any true effects that might be targeted by interventions. The overall goal of this project is to assess causality between gut microbiota and atherosclerotic disease and to provide easily accessible biomarkers for an atherosclerosis-enhancing gut microbiota. To this end, the research program has three main objectives:
- Identification of gut microbiota characteristics associated with atherosclerosis measured by coronary computed tomography angiography and high-resolution carotid ultrasound in a population-based sample of 10,000 individuals and through prospective follow-up for myocardial infarction and ischemic stroke. The microbiota will be characterized by next-generation sequencing techniques in faecal samples.
- Identification of plasma biomarkers associated with an atherosclerosis- enhancing microbiota using comprehensive metabolomics profiling of 800 named metabolites in plasma from 800 individuals with replication in additional 800 individuals
- Clarification of the causal effects of gut microbiota characteristics on atherosclerosis, myocardial infarction and stroke by development of novel genetic instruments and applying Mendelian Randomization analysis
The project is expected to lead to the identification of characteristics of an atherosclerosis-enhancing gut microbiota and associated plasma biomarkers that may open up new avenues for effective prevention of atherosclerotic disease.
We are active in using traditional epidemiology including two papers reaching high public attention in 2015. One of these led by Prof. Ingelsson investigated novel predictors of mortality (Altmetric 535, top 5% of all research scored) and the other one led by Dr Fall investigated the association of animal exposure on childhood asthma risk (Altmetric 430, top 5% of all research scored). In 2017, the paper by Mwenya Mubanga from our group reached an Altmetric score of >2000, top 1% of all reserach scored. We continue to work on these two unique resources, the UK Biobank (502,000 participants) and the Swedish national registers with other important public health questions.
Significance and novelty
Our research program combines comprehensive characterization in humans using both -omics methods and detailed phenotyping, with experiments in both in vitro and in vivo model systems in an integrative fashion providing a translation-back translation framework. We have access to unique study materials, state-of-the art methods, and a strong track record of successful projects in this field. Our work is anticipated to lead to new important insights into the pathophysiology of obesity, lipid metabolism, type 2 diabetes and cardiovascular diseases, and to new approaches to prevention and treatment that could have a huge impact on public health.