Introduction

Unhealthful lifestyles underpin much of the burden of cardiometabolic disease affecting contemporary societies. In general, diet and exercise therapies focused on weight loss substantially lower disease risk and may slow disease progression. However, clinicians and patients often view diet and exercise as a stepping stone to drug therapy, primarily because even patients who adhere to lifestyle advice often respond inadequately. This is in part because lifestyle therapy is often prescribed in a generic fashion, despite individual biology impacting treatment response. Thus, there may be tremendous untapped potential to improve patient care by personalizing diet and exercise recommendations.

Goals

Our overarching objective is to discover and optimise measurable biomarkers that can be used to stratify patient populations into subgroups that can be treated more effectively with targeted lifestyle therapies, at lesser cost and with fewer adverse events than conventional approaches allow.

There are three integrated components to my research programme:

1. Epidemiology: observational studies focused on i) explicitly testing gene-lifestyle interaction effects for candidate loci and ii) the investigation of foetal programming and early development in genetically-predisposed populations
2. Functional genomics: ex vivo experiments focused on i) the identification of diet or exercise-responsive regulatory elements within the human genome and ii) DNA editing at candidate loci to perturb the effects of lifestyle mimetics on metabolic and epigenomic readouts
3. Randomized controlled trials: lifestyle intervention studies focused on determining the clinical relevance of gene-lifestyle interaction effects in i) existing diabetes prevention and progression trials and ii) new, specially designed genotype-based recall trials

Impact

The work undertaken by the Genetic and Molecular Epidemiology (GAME) Unit has focused predominantly on characterizing the joint effects of lifestyle and genomic variation in obesity, type 2 diabetes, and cardiovascular disease. The use of data generated through this and ongoing work to help personalized preventive and therapeutic interventions is now at the forefront of the Unit’s agenda. Much of this work is at a proof-of-concept stage, but the ultimate objective is to generate new knowledge that will facilitate tailored lifestyle and drug therapies for the prevention and treatment of complex cardiometabolic diseases like type 2 diabetes, gestational diabetes and cardiovascular disease. The tailoring of such therapies will, it is hoped, improve treatment effectiveness, reduce costs and unnecessary side effects, and improve patient adherence.

Highligths