Functional genetics in cellular models of cardiovascular disease
We are using human induced pluripotent stem cells (hiPSC) to derive cell types that play key roles in the aetiology of cardiovascular disease. These cellular models allow the characterisation of functional effects of genetic risk variants in the appropriate cellular and environmental context. For example, in collaboration with the Wellcome Sanger Institute, we are identifying and characterising the effect of modified low-density lipoprotein (LDL) exposure on gene expression and splicing in macrophages. Uptake of LDL is a critical step in atherosclerosis, the main cause of coronary artery disease.
Illuminating gene-phenotype associations using recall-by-genotype studies
We are conducting genotype-directed “deep phenotyping” of volunteers who carry pivotal genetic variants associated with cardiovascular disease. The concept is to identify molecular and cellular biomarkers in a causal pathway that differ between variant carriers and non-carriers by using genetic information to help recreate informative biological gradients. Such recall-by-genotype studies can help elucidate the relationship between genetic variants and disease risk. All studies are performed as part of the NIHR BioResource, a panel of over 100,000 volunteers.
Multi-omics approaches to cardiovascular disease
We are mapping genome-wide the association of genetic variants with a range of high-dimensional cardiovascular intermediate traits, including soluble proteins, transcripts and metabolites. Then, we are performing integrated analyses to highlight molecular pathways and processes implicated in cardiovascular disease. This approach has the potential to connect biological data layers and to reveal coordinated, functional relationships between genes and disease.
Functional investigation of genetic determinants of blood cell traits
We are using genome-editing techniques to advance the mechanistic understanding of candidate functional variants and genes associated with red blood cell traits. Such molecular investigations are needed to establish the function of these genes in iron homeostasis and metabolism and its potential role in related complications, including iron deficiency anaemia and sickle cell disease. This research theme is part of the NIHR Blood and Transplant Research Unit in Donor Health and Genomics.
Epigenome-wide analyses of immune cell function
We are studying how epigenetic modifications influence gene regulation in immune cells. Such modifications, including DNA methylation, are cell type-specific and induce stable changes in gene expression that are heritable during cell division. These changes can function as mediators in response to environmental stimuli, and contribute to disease development and progression. As part of the BLUEPRINT Consortium, we are uncovering the role of epigenetic variation on immune cell function during homeostasis and immune-related disorders such as type 1 diabetes.
The Integrative Human Genomics Team is multi-disciplinary and works closely with research groups at the Wellcome Sanger Institute, BHF Cambridge Centre for Cardiovascular Research Excellence and NIHR Cambridge Biomedical Research Centre, as well as other partners in academia and industry.
Our research projects have been generously supported by the British Heart Foundation, National Institute of Health Research and Wellcome.