Functional genetics in cellular models of cardiovascular disease
We use 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 investigating the impact of modified low-density lipoprotein (LDL) on gene expression in macrophages. Uptake of modified LDL is a critical step in atherosclerosis, the main cause of coronary artery disease.
Illuminating gene-phenotype associations using recall-by-genotype studies
We conduct genotype-directed deep phenotyping of healthy volunteers who carry pivotal cardiovascular disease variants versus those who do not. The concept is to identify molecular phenotypes in a causal pathway that differ between the relevant genotypic groups by using genetic information to help recreate informative biological gradients. Such recall-by-genotype studies can help elucidate the relationship between genetic variation and disease risk. All studies are performed as part of the NIHR BioResource, a panel of over 100,000 healthy volunteers.
Functional investigation of genetic determinants of blood cell traits
We are using genome-editing techniques to advance the mechanistic understanding of candidate functional variants associated with red blood cell traits. Such molecular investigations are needed to understand normal gene function in iron homeostasis and metabolism and its potential role in related complications, including iron deficiency anaemia. In turn, this may inform biomarkers applied to donors who undergo repeated blood donations. 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 study 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 supported by the BHF Cambridge Centre for Cardiovascular Research Excellence [RE/13/6/30180, RG/13/13/30194], NIHR Cambridge Biomedical Research Centre, and Wellcome [105602/Z/14/Z].