Harrap laboratory: Genetic physiology
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The research interests of our group are varied, but tied to a common theme that of understanding the genetics behind common complex diseases and phenotypes – known these days as systems biology. Our research targets include cardiovascular disease and its risk factors, adult height, and androgenetic alopecia (common baldness). Our team of research fellows, biostatisticians, postgraduate research students and research assistants are employing the latest research methods, laboratory equipment and novel statistical methods to define DNA variation that contribute to cardiovascular risk, height and baldness.
In 1990 we established the Victorian Family Heart Study (VFHS) and after 6 years we successfully recruited approximately 3000 healthy adults who comprised about 800 families (each of mum, dad and at least 1 natural offspring). These families were enriched by the inclusion of families with twins. For this we are indebted to Professor John Hopper and the Australian Twin Registry. The result is a unique resource for studying the genetic and environmental factors that determine simple traits such as blood pressure, heart rate, weight, height, cholesterol, baldness and fibrinogen. To do so we have taken advantage of the most modern technology and brought together a team with skills in molecular biology and genetic biostatistics. The VFHS is renown internationally for its discoveries in relation to blood pressure and the Y chromosome, baldness and the androgen receptor gene, the genetics of height and ongoing studies of cardiovascular risk factors.
To complement the VFHS focus on risk factors, we established the Acute Myocardial Infarction Genetic Origins (AMIGO) Study looking at the genetics of heart attack (acute coronary syndrome). This was one of the first studies in the world to report genome wide linkage for this condition that remains the single most common cause of death. Although a relatively small study, the care with which it was undertaken maximised the outcomes and our results have been corroborated by subsequent meta-analyses.
We have collaborative roles major clinical trials such as ANBP2, PROGRESS and ADVANCE. These trials have made major contributions to modern clinical practice in the prevention of cardiovascular disease and have influenced treatment guidelines around the world. We continue with genetic research as substudies within these trials.
To understand the genetic basis of heart size (which after age is the single most important cardiovascular risk factor), I initiated series of breeding studies in rats in 1989. This resulted in the first identification by genome wide scanning of a gene that controls heart size independent of blood pressure. The breeding continued to produce a new strain of rat - Hypertrophic Heart Rats (HHR) - that has normal blood pressure but a big heart and develops heart failure. Our recent studies with Prof Leanne Delbridge here at the University of Melbourne and Prof Fadi Charchar at the University of Ballarat are making major headway into understanding the pathophysiology of cardiac hypertrophy and heart failure from the molecular, cellular and whole organ perspective.
We are also pursuing the answers to a fascinating research question posed by our studies 30 years ago – why does brief treatment of the Spontaneously Hypertensive Rat (SHR) with a specific form of antihypertensive treatment result in a lifelong reduction in high blood pressure? Since those early days the technology and bioinformatics has developed to a stage where we can solve this question.
The funding for the human and experimental research has been generously provided from a variety of sources including the National Health and Medical Research Council, the Victorian Health Promotion Foundation, the Australian Research Council, the National Heart Foundation, the Cabrini Medical Education & Research Foundation and the Clive & Vera Ramaciotti Foundation.
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For further information about this research, please contact Professor Stephen Harrap