This theme covers three major areas of work:
1. Molecular genetics of inherited heart disorders
Previous work on inherited cardiomyopathies led to the hypothesis that Hypertrophic Cardiomyopathy (HCM) is a disease of energy compromise. This is supported by biochemical and biophysical, mouse model and clinical studies, together with demonstration of the first non-sarcomeric disease gene for HCM, y2 AMPK. The “energetics hypothesis” will be tested in rodent models and by proof-of-principle randomised controlled trials in man. Dissection of downstream pathways will require integration of our reductionist myofilament experiments with cell physiology studies. Direct effects on cardiomyocyte calcium-handling will be investigated as will novel genetic findings implicating perturbations in sarcomere:nucleus hypertrophy signalling. Findings in mouse models with cardiac development defects arising from gene-targeted and ENU screens will be translated by human genetic analyses of congenital heart disease (CHD). The hypothesis to be tested is that rare alleles in genes controlling heart development and left/right patterning underlie common (i.e. non-syndromic/non-Mendelian) forms of CHD in man.
2. Genetic susceptibility to diseases inherited as complex traits
The combination of the genetics and genomics expertise, statistical genetics/bioinformatics capabilities of the Wellcome Trust Centre for Human Genetics and the epidemiological resources of the Clinical Trials Service Unit (CTSU), has begun to yield linkage and association evidence for genes determining quantitative traits, and disease endpoints, in both myocardial and vascular disease. We will conduct a third phenotypic analysis (MRI based) on our longitudinal family study investigating genetic determinants of quantitative cardiovascular risk factors (the HTO study) and will then proceed to genome-wide association analysis (GWAS). The PROCARDIS study in coronary artery disease has completed a genome wide linkage analysis on an unprecedented scale (identifying and replicating a novel MI susceptibility locus on Chr. 17) and will complete a definitive 1M SNP GWAS shortly. Unrivalled quantitative trait and intermediate phenotype data, including novel metabolomic and peptidomic analyses, will greatly enhance the informativeness of the collections.
3. Genetic and genomic epidemiology of coronary artery disease (CAD) and risk factors
Oxford is poised to take a leading role in population-scale genetic and genomic analyses of CAD. Emphasis will be on robust, large scale, population studies based on collections at the CTSU, with analysis of genetic determinants of disease endpoints, drug response and intermediate phenotypes.
PI's involved in this research theme:
Prof Hugh Watkins - (Theme Leader)
Prof Shoumo Bhattacharya
Dr Robert Clarke
Dr Ben Davies
Prof Peter Donnelly
Prof Martin Farrall
Dr Jemma Hopewell
Dr Sarah Parish
Dr Charles Redwood