Physiological Genomics and Medicine

The research of the Physiological Genomics and Medicine Group uses information and technologies from the Human Genome Project to improve understanding of the molecular basis of common diseases and to find new ways of diagnosing these disorders and predicting which individuals will develop them. The approaches used have found new genes underlying the common Metabolic Syndrome which predisposes to late-onset diabetes and coronary heart disease, and also showed that variation in the number of gene copies carried by an individual can be a cause of kidney failure in the common human condition systemic lupus. These findings suggest new ways of disease diagnosis and new targets for drug therapy of these conditions.

The research of the Physiological Genomics and Medicine Group has combined the use of classical genetics with genome technologies for gene discovery and understanding of gene function in common human disorders including the metabolic syndrome, systemic lupus and autoimmune glomerulonephritis. Several years ago we pioneered a new approach for identification of complex trait genes, combining the classical genome-screen technique with new DNA microarray technology for global measurement of gene expression. The approach led us to identify a defective gene, Cd36, that causes insulin resistance and hypertriglyceridaemia in spontaneously hypertensive rats (Aitman et al 1999, Nature Genet 21:76-83). Cd36 is one of the first genes for a complex mammalian trait to be identified in a genetic linkage study. Following these results, we defined an evolutionary role for the Cd36 gene in African and Asian populations (Aitman et al 2000, Nature 405:1015-1016) and used mutation screening to identify the first family in whom type 2 diabetes is caused by Cd36 deficiency. More recently we have used gene expression profiling, linkage analysis and bioinformatics to identify control points and gene networks in the Metabolic Syndrome (Hubner et al 2005, Nature Genet 37:243-53).In the last year, we have carried out genetics studies of autoimmune glomerulonephritis and have shown that a new type of genomic sequence variation, gene copy number variation, is a cause of autoimmune glomerulonephritis in rats and in the common human disease systemic lupus erythematosus (Aitman et al 2006, Nature 439:951-5). This is the first description of structural variation in the genome as a cause of autoimmune disease and has led many laboratories across the world to test for structural variation in other autoimmune disorders.||The outcome of these studies has considerable potential impact on clinical practice. The positional cloning of genes for common human diseases such as metabolic syndrome and autoimmune glomerulonephritis, and the finding of new types of genomic sequence variation as a cause of autoimmune diseases has led to the search for new diagnostic tests based on the genes and allelic variants identified. We are now using new genomic techniques including high throughput genotyping, sequence detection and microarray-based measures of gene expression and gene copy number. In addition, the systems approaches we have taken to defining disease states such as hypertension and dyslipidaemia are an example of new strategies for drug development that focus on regulatory pathways as well as individual genes.