Hugh Watkins MD, PhD, FRCP, FMed Sci

Field Marshal Alexander Professor of Cardiovascular Medicine, Honorary Consultant in Cardiology and General Medicine, Head of Department
Professor Watkins is also the Director of the British Heart Foundation Research Excellence Award at the University of Oxford.

Molecular Genetics and Molecular Biology of the Heart Muscle Disease/Molecular Genetics of Complex Cardiovascular Phenotypes

Research Themes

Divisional Themes

Genetics and Genomics
Cardiovascular Science

Selected Publications

Broadbent H M, Peden J F, Lorkowski S, Goel A, Ongen H, Green F, Clarke R, Collins R, Franzosi M G, Tognoni G, Seedorf U, Rust S, Eriksson P, Hamsten A, Farrall M, and Watkins H (2007) Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked, SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet.

Petersen Steffen E, Jerosch-Herold Michael, Hudsmith Lucy E, Robson Matthew D, Francis Jane M, Doll Helen A, Selvanayagam Joseph B, Neubauer Stefan, and Watkins Hugh (2007) Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation, 115(18):2418-25.

Farrall Martin, Green Fiona R, Peden John F, Olsson Per G, Clarke Robert, Hellenius Mai-Lis, Rust Stephan, Lagercrantz Jacob, Franzosi Maria G, Schulte Helmut, Carey Alisoun, Olsson Gunnar, Assmann Gerd, Tognoni Gianni, Collins Rory, Hamsten Anders, and Watkins Hugh (2006) Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17. PLoS Genet, 2(5):e72.

Mirza Mahmooda, Marston Steven, Willott Ruth, Ashley Christopher, Mogensen Jens, McKenna William, Robinson Paul, Redwood Charles, and Watkins Hugh (2005) Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J Biol Chem, 280(31):28498-506.

Ashrafian Houman, Redwood Charles, Blair Edward, and Watkins Hugh (2003) Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion. Trends Genet, 19(5):263-8.

Cardiomyopathy Papers

Petersen Steffen E, Jerosch-Herold Michael, Hudsmith Lucy E, Robson Matthew D, Francis Jane M, Doll Helen A, Selvanayagam Joseph B, Neubauer Stefan, and Watkins Hugh (2007) Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation, 115(18):2418-25.

Robinson Paul, Griffiths Peter J, Watkins Hugh, and Redwood Charles S (2007) Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. Circ Res, 101(12):1266-73.

Mirza Mahmooda, Marston Steven, Willott Ruth, Ashley Christopher, Mogensen Jens, McKenna William, Robinson Paul, Redwood Charles, and Watkins Hugh (2005) Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J Biol Chem, 280(31):28498-506.

Ashrafian Houman, Redwood Charles, Blair Edward, and Watkins Hugh (2003) Hypertrophic cardiomyopathy:a paradigm for myocardial energy depletion. Trends Genet, 19(5):263-8.

Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, Salmon A, Ostman-Smith I, and Watkins H (2001) Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet, 10(11):1215-20.

Complex Trait Papers

Farrall Martin, Green Fiona R, Peden John F, Olsson Per G, Clarke Robert, Hellenius Mai-Lis, Rust Stephan, Lagercrantz Jacob, Franzosi Maria G, Schulte Helmut, Carey Alisoun, Olsson Gunnar, Assmann Gerd, Tognoni Gianni, Collins Rory, Hamsten Anders, and Watkins Hugh (2006) Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17. PLoS Genet, 2(5):e72.

Mayosi Bongani M, Avery Peter J, Baker Michelle, Gaukrodger Nicole, Imrie Helen, Green Fiona R, Farrall Martin, Watkins Hugh, and Keavney Bernard (2005) Genotype at the -174G/C polymorphism of the interleukin-6 gene is associated with common carotid artery intimal-medial thickness: family study and meta-analysis. Stroke, 36(10):2215-9.

Watkins H (2004) A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease Eur.J.Hum Genet, 12:770-774.

Wheeler Jeremy G, Keavney Bernard D, Watkins Hugh, Collins Rory, and Danesh John (2004) Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies. Lancet, 363(9410):689-95.

Mayosi B M, Keavney B, Kardos A, Davies C H, Ratcliffe P J, Farrall M, and Watkins H (2002) Electrocardiographic measures of left ventricular hypertrophy show greater heritability than echocardiographic left ventricular mass. Eur Heart J, 23(24):1963-71.

Email	hugh.watkins@cardiov.ox.ac.uk
Tel	+44 (0)1865 234657
Fax	+44 (0) 1865 234658
Email (PA)	kathryn.smith@cardiov.ox.ac.uk

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

HW lab 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 John Peden, 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: Kimberley Adams, Houman Ashrafian, Mohamed Bellahcene, Gabor Czibik, Anuj Goel, Anna Helgadottir, Henrik Isackson, Shapour Jalilzadeh, Yanyan Jiang, Theo Kyriakou, Farah Nematkhah, Halit Ongen, John Peden, Katalin Pinter, Paul Robinson, Violetta Steeples, Arash Yavari.

Sources of Funding

Biography

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.

Cardiovascular

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