FUNDER
Colleges
Hugh Watkins
FRS FMedSci
Radcliffe Professor of Medicine
- British Heart Foundation Professor of Cardiovascular Medicine
- Honorary Consultant in Cardiology and General Medicine
- Principal Investigator of CureHeart
- Director of the BHF Centre for Research Excellence
Molecular Genetics and Molecular Biology of the Heart Muscle Disease/Molecular Genetics of Complex Cardiovascular Phenotypes
My interest is in using molecular genetic analysis of cardiovascular disease as a tool to define disease mechanisms and therapeutic targets. I have had a longstanding focus on inherited heart muscle diseases, in particular hypertrophic cardiomyopathy, which is a relatively common Mendelian condition which puts affected individuals at risk of sudden cardiac death. My group's work, using molecular biological, model organism and clinical research approaches, has lead to the idea that energy compromise is a key disease mechanism; clinical trials are underway to test new medical therapies based on this finding. Our work on genetic causes of ‘sudden cardiac death’ syndromes has been translated into clinical practice through the Oxford BRC, leading to an NHS commissioned national DNA diagnostic service. This area of my work is integrally linked with the groups of Dr. Charles Redwood and Dr. Houman Ashrafian as we have worked closely together for many years.
I also lead a research group investigating susceptibility genes for coronary artery disease, now the main cause of premature mortality worldwide. With colleagues in Oxford (Profs Farrall and Collins) and in Europe (Prof Hamsten, Karolinska) I established the Procardis study to assemble the large scale clinical collections needed to tackle this challenge; I have since chaired a large international collaboration in this area (the C4D Consortium). Recent findings include evidence that lipoprotein Lp(a) levels are causally related to coronary disease risk and identification of multiple novel common susceptibility variants for coronary artery disease risk. This work is now entering an exciting phase where we can use functional genomic tools to understand new biology, thus drawing on some of the approaches we have developed in our Mendelian genetic work.
Key publications
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Association analyses based on false discovery rate implicate new loci for coronary artery disease.
Journal article
Nelson CP. et al, (2017), Nat Genet, 49, 1385 - 1391
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Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
Journal article
Yavari A. et al, (2016), Cell Metab, 23, 821 - 836
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Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.
Journal article
Walsh R. et al, (2017), Genet Med, 19, 192 - 203
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A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.
Journal article
Nikpay M. et al, (2015), Nat Genet, 47, 1121 - 1130
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Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction.
Journal article
Hastings R. et al, (2016), Circ Cardiovasc Genet, 9, 426 - 435
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Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.
Journal article
Ashrafian H. et al, (2012), Cell Metab, 15, 361 - 371
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Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.
Journal article
Abozguia K. et al, (2010), Circulation, 122, 1562 - 1569
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Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
Journal article
Clarke R. et al, (2009), N Engl J Med, 361, 2518 - 2528
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
Journal article
Speliotes EK. et al, (2010), Nature Genetics, 42, 937 - 948
Recent publications
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AnALPK3truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten
Preprint
Leinhos L. et al, (2024)
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Genetic therapies for cardiomyopathy: survey of attitudes of the patient community for the CureHeart project.
Journal article
Ormondroyd E. et al, (2024), Eur J Hum Genet, 32, 1045 - 1052
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An autosomal dominant cardiac arrhythmia syndrome, ST Depression Syndrome, is caused by thede novocreation of a cardiomyocyte enhancer
Preprint
de Villiers CP. et al, (2024)
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Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.
Journal article
Coleman JA. et al, (2024), Cardiovasc Res, 120, 914 - 926
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Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.
Journal article
Coats CJ. et al, (2024), Journal of the American Heart Association