Integrative genomics in cardiovascular medicine
Teasing apart the genetic mechanisms underlying common diseases is afundamental priority of much biomedical research today. From obesity tocancer, unpicking this lock is seen as the key to the future ofmedicine. But the basis of many of the most common diseases is notstraightforward. Classical genetic approaches often fail to reveal thetrue complexity. Two new papers published in CardiovascularResearch by researchers at the CSC have addressed the emergingimportance of integrative genomics – approaches that look at multiplelayers of data, from DNA sequences to protein interactions andmetabolic pathways – in cardiovascular medicine.
Researchers from the Cardiovascular Magnetic Resonance Imaging and Genetics and Integrative Genomics and Medicine Groups have published a review of the state-of-the-art of integrative genomics in cardiovascular medicine.“It’s not just about finding genes, but understanding the context in which the genes operate,” explains co-author Enrico Petretto. “That’s where modern genomics is going.” Integrative genomics tackles this target. Data are obtained on not only genetic sequence variation, but differences in transcriptional regulatory networks, protein interactions and the metabolic pathways they ramify; and ultimately the disease phenotype. This paints a much broader view of the factors affecting a disease.
“When studying a disease, you have to think about all of the molecularand clinical factors,” says Petretto. “It requires a lot of modelling,bioinformatics and computation, because all of these vast data must beanalysed together.” Putting their philosophies into practise, the teampublished a research paper, dealing specifically with hypertension. Theresearch identified 700 genes in rats that played a role inhypertension, with conserved parallels in humans. “Using the rat model,we can look at the system as a whole,” says Petretto. “Genetic studiesin humans can identify a few genes associated genetically with bloodpressure, but not much more. We look at the system as a whole, to seeif a gene is active in a particular tissue, whether it is interactingwith other genes, and if it is associated with blood pressurevariation.” The plethora of data produced in the rat can then becompared to genome-wide studies in humans to reveal what role thesefactors might be playing in hypertension susceptibility and development.
Previous genome-wide association studies (GWAS) in humans hadidentified only a few genes with relatively large effect inhypertension. But, says Petretto, this “genetic-association”information alone is insufficient to explain the variability of bloodpressure found in patients. “Human GWAS reveal the tip of the iceberg.But what about everything underneath? The regulation of hypertension isnot explained by these factors alone – we have to look at the wholeiceberg.” By generating a large list of interacting genes (e.g. genenetworks), this research begins to fill in the large gaps inunderstanding. “The genes individually don’t all have large effects,”cautions Petretto, “but they do each play a role. And among these genesare some ‘master regulators’ that we discovered in the rat, which havea strong influence over the rest of the genetic network. This is therest of the iceberg.”
- Ware, J. S., Petretto, E., Cook, S. A., (2012). Integrativegenomics in cardiovascular medicine. Cardiovascular research. Abstract
- Langley, S. R., Bottolo, L., Kunes, J., Zicha, J., Zidek, V.,Hubner, N., Cook, S. A., Pravenec, M., Aitman, T. J., Petretto, E.,(2012). Systems-level approaches reveal conservation of trans-regulatedgenes in the rat and genetic determinants of blood pressure in humans.Cardiovascular research. In press Abstract
Image Credit: illustrations available under creative commons license,(CC-BY-2.0, courtesy of Wellcome Library, London)