Genetic and Molecular Epidemiology - GAME
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.
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:
- 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
- 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
- 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
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.
European Research Council Consolidator Award (1.87m EUR): Novel Approach to Systematically Characterize Exercise- and Nutrient-responsive genes in Type 2 diabetes & cardiovascular disease (NASCENT). 2016-2021
Innovative Medicines Initiative grant (46m EUR): Diabetes Research on Patient Stratification (DIRECT). Innovative Medicines Initiative (IMI_JU_2010_03_06). 2012-2019 (Coordinators: Ruetten/Pearson, Sanofi-Aventis/Univ Dundee; Work-package leader: Franks, Lund)
Koivula RW, Heggie A, Barnett A, Cederberg H, Koopman ADM, Ridderstråle M, Rutters F, Vestergaard H, Gupta R, Herrgård S, Perry M, Rauh S, Siloaho M, Teare H, Bell JD, Brunak S, Frost GS, Jablonka B, Mari A, McDonald T, Dekker JM, Hansen T, Hattersley AT, Laakso M, Pedersen O, Koivisto V, Ruetten H, Walker M, Pearson E, Franks PW. Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT consortium Diabetologia. 57(6):1132-42. 2014
(R Koivula was a PhD student in the GAME Unit)
Ahmad S, Rukh G, Varga TV, Ali A, Kurbasic A, Shungin D, Ericson U, Koivula RW, Chu AY, Rose LM, Ganna A, Qi Q, Stančáková A, Sandholt C, Elks CE, Curhan G, Jensen MK, Tamimi RM, Allin KH, Jørgensen T, Brage S, Langenberg C, Aadahl M, Grarup N, Linneberg A, Paré G, InterAct Consortium, DIRECT Consortium , Magnusson PKE, Pedersen NL, Boehnke M, Hamsten A, Mohlke KL, Pasquale LR, Pedersen O, Scott RA, Ridker PM, Ingelsson E, Laakso M, Hansen T, Qi L, Wareham NJ, Chasman DI, Hallmans G, Hu FB, Renström F, Orho-Melander M, Franks PW. Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry. PLoS Genetics. 9(7):e1003607. 2013
(A Ahmad was a PhD student in the GAME Unit)
Shungin D, Winkler TW, Croteau-Chonka DC, …[~300 authors]… Franks PW*, Ingelsson E*, Heid IM*, Loos RJ*, Cupples LA*, Morris AP*, Lindgren CM*, Mohlke KL*. New genetic loci link adipocyte and insulin biology to body fat distribution. Nature. 12;518(7538):187-96. 2015
* Writing group (D Shungin was a PhD student in the GAME Unit)