Hugh Watkins

Research Base:  BHF Molecular Cardiology Laboratory, Henry Wellcome Building of Genomic Medicine and Department of Cardiovascular Medicine laboratories in the West Wing of the John Radcliffe Hospital. Laboratory manager:  Phil Townsend Molecular Genetics and Molecular Biology of Heart Muscle Disease   Molecular genetics:  Our studies focus on the molecular basis of monogenic cardiomyopathies to provide insight into disease processes in heart muscle.  Most disease-genes for hypertrophic cardiomyopathy (HCM) encode contractile proteins, but an important new finding was our demonstration of the first non-sarcomeric disease-gene for HCM: the y-2 subunit of the AMP-activated protein kinase (AMPK).  Studies in inherited dilated cardiomyopathy (DCM) have also lead to the identification of sarcomeric mutations, but also have identified abnormalities in calcium-handling proteins. Functional analysis: Biochemical, biophysical, and gene-targeting analysis of mutant contracile proteins have lead us to propose that there is no unifying defect in contractility underlying HCM.  Instead, we have postulated that HCM is a disease of energetic compromise (because the various mutations increase the energy cost of force production). This hypothesis has been supported by clinical MR spectroscopy measurements in patients and has implications, which we are now exploring, for treatment and for common forms of cardiac hypertrophy and failure. Translational research: The disease-gene indentification programme in our research lab has now been translated into the first NHS molecular diagnostic service for inherited "sudden cardiac death syndromes". Main local collaborators: Dr Charles Redwood, Professor Stefan Neubauer, Dr Ed Blair, Professor Barbara Casadei, Professor Chris Ashley. Main external collaborators: Professor Bill McKenna (UCL), Professor Steve Marston (NHLI, London) Professor David Carling (Imperial). Molecular Genetics of Complex Cardiovascular Phenotypes Recognising that our monogenic analyses have moved into functional and translational phases, the groups' human genetics activities now focus on important cardiovascular complex traits.  We have intensively phenotyped a collection of extended families (the Oxfordshire Family Blood Pressure Study ) to explore heritability, candidate gene analysis, and genome-wide screens for a number of cardiovascular intermediate phenotypes.  Published work has illustrated heritability and genetic determinants of plasma CRP levels (an important new risk factor for coronary disease) and of left ventricular hypertrophy.  Ongoing studies are based on genome-wide linkage and association data (in collaboration with B. Keavney, B. Mayosi, M. Lathrop and M. Farrall). Coronary artery disease:  The PROCARDIS Study  consortium has, over the last seven years, assembled the largest collection worldwide of families with early myocardiac infarction.  This five-centre, four-country, consortium (with pharmaceutical and biotechnology partners) is coordinated by Professor Watkins with Fiona Green and Martin Farrall .  A substantial genome-wide linkage screen has been completed and linkage loci are being evaluated and a high-density genome-wide SNP analysis is near completion.  A unique aspect for the collection is a very large trio family-based population for TDT analysis (1200 trio families) which is unrivalled in this late onset disorder.  The major investment over recent years should yield exciting opportunities for genetic and functional analysis over the next five years. Main local Collaborators:  Professor Martin Farrall, Professor Rory Collins Main External Collaborators:  PROCARDIS Partners, Professor Bernard Keavney, Professor Bongani Mayosi. Group Members:  Houman Ashrafian, Mohamed Bellahcene, Gabor Czibik, Anuj Goel, Katja Gehmlich,  Henrik Isackson, Shapour Jalilzadeh, Theo Kyriakou, Farah Nematkhah, Katalin Pinter, Paul Robinson, Violetta Steeples, Alex Stockenhuber, Arash Yavari.

Prof Hugh Watkins is the Field Marshal Alexander Professor of Cardiovascular Medicine at the University of Oxford.  He is Head of the Department of Cardiovascular Medicine and Honorary Consultant in Cardiology and General Medicine at the John Radcliffe Hospital, Oxford.  Professor Watkins directs the BHF Molecular Cardiology Laboratory in the Wellcome Trust Centre for Human Genetics and is also Director of the British Heart Foundation Centre of Research Excellence at Oxford , one of four such programmes in the UK. His expertise is in molecular genetic analysis of cardiovascular disease as a tool to define disease mechanisms and therapeutic targets.  He is best known for his work on inherited heart muscle diseases, in particular hypertrophic cardiomyopathy where his work has lead to the idea that energy compromise is a key disease mechanism. His work on genetic causes of ‘sudden cardiac death’ syndromes has been translated into clinical practice as part of a Department of Health funded ‘Genetics Knowledge Park’ leading to commissioning of a national DNA diagnostic service. He also investigates susceptibility genes for coronary artery disease and chairs a large international collaboration in this area, including pharmaceutical and biotech partners, with funding from the European Commission. He is a Fellow of the Academy of Medical Sciences, a Fellow of the American Heart Association and he is Associate Editor of Circulation Research.