The goal of this research theme is to translate epidemiological findings based on ‘omics approaches and conventional risk factors into biological insights and intervention strategies to improve public health. This theme comprises the following key research areas: Integrative Genomics, Recall-by-Genotype and Clinical Epidemiology.

Integrative Genomics

The goal is to identify and characterise causal biological pathways in cardiovascular disease. Population-scale genomic analyses have transformed our understanding of the contribution of genetic variation to the risk of cardiovascular disease. However, a major challenge in unlocking the potential of these genomic studies is in uncovering the molecular chain of events from genetic variation to clinical events. To tackle this challenge, the Integrative Genomics Team led by Dr Dirk Paul combines systematic computational and experimental approaches to translate the genetic associations into causal biology. The Team applies cutting-edge technology to elucidate the molecular, cellular and physiological underpinnings of candidate causal variants and genes, including CRISPR/Cas9 genome editing in cellular models and recall-by-genotype mechanistic studies in healthy volunteers. This work, which integrates genetic epidemiology, functional genomics/epigenomics and clinical medicine, enables a better understanding of the aetiology of cardiovascular disease and informs the development of new therapeutics.

Recall-by-Genotype

The goal is to translate genomic discoveries in cardiovascular disease into causal mechanisms using human experimental medicine 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 and inform novel treatment strategies.

The volunteers who take part in our studies are recruited from the NIHR BioResource, a national panel of over 200,000 volunteers (with or without health conditions) who are willing to be contacted to participate in research studies, investigating the links between genes, the environment, health and disease. We currently have three studies ongoing/planned:

• CADBIO – Molecular investigation of genetic factors in CArdiovascular Diseases using a BIOresource of healthy volunteers (lead investigator Dr Dirk Paul)
• GENBIO – Molecular investigation of GENetic factors in cardiovascular and immune-related traits and diseases using a BIOresource of healthy volunteers (lead investigator Dr Dirk Paul)
• AADBIO – Clinical investigation of genetic variants associated with Aortic Aneurysm and Dissection using a BIOresource of healthy volunteers (lead investigator Dr Seamus Harrison)

Learn more about our portfolio of recall-by-genotype studies here.
As part of these studies, we have given presentations at public events hosted by the Cambridge Festival, NIHR BioResource and NIHR Blood Transplant Research Unit. View a recording of our Cambridge Festival 2021 presentation (“The Role of Genetics in Cardiovascular Health and Disease”) and panel discussion here.

Clinical Epidemiology

The goal of this research theme is to identify the genetic and clinical features of aortic dissection and to develop screening strategies to prevent aortic growth and rupture.

Aortic dissection is a potentially devastating condition that occurs suddenly and without warning. There is a strong genetic component to the disease with high blood pressure and cigarette smoking considered to be major clinical risk factors. The long-term outcomes vary greatly between individuals who survive the initial event. In some patients, the aorta remodels and a quiescent course ensues. In other patients, the aorta enlarges over time and can rupture.

The Aortic Dissection Rare Disease Study (lead investigator Dr Seamus Harrison) is a multi-centre study into the genetic, imaging and clinical risk factors of aortic dissection. It is run via the NIHR BioResource, recruiting affected patients and, in some cases, their first-degree relatives into a Rare Disease BioResource. This provides a resource for researchers to conduct studies to better understand and ultimately manage this important disease. Further details about the study can be found here.

In another study, we will use data from large population cohorts to integrate genomic medicine, aortic screening and artificial intelligence to maximise the efficiency of aortic screening. Screening asymptomatic individuals allows the identification of the condition at an early stage and can inform strategies to prevent aortic growth and rupture. We will build risk prediction models for aortic aneurysm using polygenic scores and deep phenotype data (analysis lead Dr Martin Kelemen; lead investigator Dr Seamus Harrison).