Functional Variants Of RUNX2 Related To Bone Density
Funder
National Health and Medical Research Council
Funding Amount
$451,938.00
Summary
Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ....Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ancestral form of this gene. We now need to know how this change in this promoter alters bone density and we are following up on observations that other important transcription factors bind to the variable site in the promoter. Furthermore, we have assembled a large collection of samples from people who have had extensive measures of bone density and arthritis in order to accurately measure the impact of this gene on bone density, osteoarthritis and bone fracture. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. Such mutations in a region called the Q-repeat are rather common, 1-200 people are carriers. Our data show that these mutant proteins are not as efficient at their task of regulating other genes. We now want to know how this occurs in a molecular sense, since it is known that the Runx2 protein resides in the nucleus of the cell and interacts with many other regulators. This part of the project is being done with one of the world experts on gene regulation in bone cells. Since RUNX2 is a master regulator of the cells that make bone, this gives hope that it may be possible to alter bone formation through this master regulator.Read moreRead less
High scorers on the personality trait neuroticism are at greatly increased risk of major depression and other neurotic disorders. Neuroticism is a personality trait that shows considerable stability over adulthood. It has a strong genetic basis and it seems that the same genes also determine risk of depression, anxiety and other neuroses. By selecting twins and sibs extremely discordant and concordant (EDAC) for neuroticism we can greatly reduce the cost and increase the power to find genes infl ....High scorers on the personality trait neuroticism are at greatly increased risk of major depression and other neurotic disorders. Neuroticism is a personality trait that shows considerable stability over adulthood. It has a strong genetic basis and it seems that the same genes also determine risk of depression, anxiety and other neuroses. By selecting twins and sibs extremely discordant and concordant (EDAC) for neuroticism we can greatly reduce the cost and increase the power to find genes influencing depression. Questionnaire responses and interviews from 15,027 Australian twins and 11,389 of their family members were reviewed to identify individuals with neuroticism scores in the top and bottom 10%. These individuals were invited to participate in a structured psychiatric interview by telephone, and to give a blood sample. Participation and DNA sampling rates were high and there was minimal evident participation bias. DNA was collected from 2,926 individuals from 884 families including 1,333 EDAC sibling pairs and over 795 parents. A preliminary genome scan on one third of this sample yields several linkage peaks suggesting genes of major effect that appear to replicate findings in similar studies conducted in Holland and England. Given these results it is highly desirable that we obtain a genome scan on the remainder of selected extreme sample. Another one third of this sample is currently being genotyped in America and here we request funds to genotype the remaining third. .If we are successful in identifying genes underlying neuroticism, we will also be able to analyse their contribution to depression and anxiety. This could lead to better drug treatments.Read moreRead less
MALE OSTEOPOROSIS: A POPULATION-BASED STUDY IN GEELONG
Funder
National Health and Medical Research Council
Funding Amount
$432,645.00
Summary
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is i ....Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is increasingly being recognised in men. In Australia, 39% of all fractures occur in men and prognosis for fracture in men is worse than in women. A consequence of increasing male longevity is that osteoporosis will affect a growing number of Australian men. It is anticipated that between 1996 and 2051, the number of men with fracture will double, with a 4-fold increase in the number of male hip fractures. Unless the problem of osteoporosis in men is addressed and effective interventions are implemented, the substantial health burden imposed by age-related fractures will continue to escalate. In this case-control study of fracture risk in men, men with fractures (cases) will be identified prospectively for 3 years from radiological reports. Controls will be selected concurrently, at random from electoral rolls. Anticipated number of cases and controls are 800 and 1400, respectively. Cases and controls will be characterised for risk factors for fracture: bone density and bone geometry will be measured, serum samples collected, and diet, lifestyle and medical history documented by questionnaire. The advantage of this type of data is that information from patients with fracture will be used to tell us about the risk of fracture in healthy, unaffected men and about the characteristics of the Australian male population at risk for fracture. The information can be used in decision making for the individual and in policy making for the whole population.Read moreRead less
Australian Genomewide Association Study In Osteoporosis
Funder
National Health and Medical Research Council
Funding Amount
$882,722.00
Summary
Osteoporosis is a common condition in which bone strength is reduced due to reduced amount and quality of bone. Reduced bone strength means an increased risk of fracture. Osteoporotic fractures occur in 1 in 2 women and 1 in 3 men in their lifetime, and the likelihood of suffering osteoporotic fracture increases with age. Most of the risk of developing osteoporosis is genetic, but few of the genes involved have been identified. Our goal is to identify those genes.
Structural And Diffusion Tensor Neuroimaging In Twins Concordant And Discordant For Psychosis.
Funder
National Health and Medical Research Council
Funding Amount
$477,375.00
Summary
Measures from specialised brain scans i.e. MRI's (Magnetic Resonance Imaging) have suggested that several areas in the brain are different in those individuals who suffer from psychosis compared to those who don't. Evaluations of these brain differences have helped us better understand the nature of these illnesses. For example, frontal lobe dysfunction has been linked with the loss of ability to plan and organize information, seen in those who have schizophrenia. These measures may also help cl ....Measures from specialised brain scans i.e. MRI's (Magnetic Resonance Imaging) have suggested that several areas in the brain are different in those individuals who suffer from psychosis compared to those who don't. Evaluations of these brain differences have helped us better understand the nature of these illnesses. For example, frontal lobe dysfunction has been linked with the loss of ability to plan and organize information, seen in those who have schizophrenia. These measures may also help clarify the relationship between the genetic and environmental factors contributing to the development of these disorders. One of the best ways to investigate this relationship is the use of a twin study design. The Australian study of twins with psychosis will recruit dizygotic (DZ) and monozygotic (MZ) twin pairs in which at least one twin is affected by a psychotic disorder, plus control twin pairs matched for age, sex and zygosity. Measures derived from MRI scans will be collected in an attempt to further define specific brain regions reported to be different in psychosis. In addition Diffusion Tensor Imaging (DTI) will be used to visualize white matter tracts in the brain. The twin study design will allow us to differentiate genetic and environmental factors associated with these brain measures and help evaluate the potential for these measures to genetically define sub-groups of individuals with psychotic disorders. The identification of these subgroups would facilitate the search for susceptibility genes. Additionally, this study will help clarify the possible clinical overlap between affective (i.e. bipolar affective disorder) and non-affective (i.e. schizophrenia) psychotic disorders. The information obtained from this study has the potential to greatly improve our understanding of caustive factors in psychosis, which may also lead to earlier diagnosis and treatment, thereby improving prognosis.Read moreRead less
Implications Of Bacterial Load For Vaccine Efficacy And Antibiotic Treatment Outcomes In High-risk Populations
Funder
National Health and Medical Research Council
Funding Amount
$345,000.00
Summary
Otitis media (middle ear disease) is a common childhood infection, and a major concern in remote Aboriginal communities of the Northern Territory. For these children, otitis media commences within the first few weeks of life and progresses to perforation of the ear drum in 60% of children by 12 months of age. Few children in remote Aboriginal communities have normal ear status or normal hearing and many have conductive hearing loss, affecting language development and education. Otitis media in t ....Otitis media (middle ear disease) is a common childhood infection, and a major concern in remote Aboriginal communities of the Northern Territory. For these children, otitis media commences within the first few weeks of life and progresses to perforation of the ear drum in 60% of children by 12 months of age. Few children in remote Aboriginal communities have normal ear status or normal hearing and many have conductive hearing loss, affecting language development and education. Otitis media in these children results from infection with the bacteria Streptococcus pneumoniae, Haemophilus influenzae and-or Moraxella catarrhalis. Therefore the types of interventions we are using to combat the high prevalence of ear disease are antibiotic therapy, Streptococcus pneumoniae vaccination, and hygiene interventions. However we fear that the high load of bacteria carried by these children compromises the treatment and prevention strategies. The current proposal will test this hypothesis, and if found to be true, there will be implications for the management of otitis media. For example, dose, frequency and choice of antibiotic treatment, and vaccine schedule changes including an early dose or a booster dose.Read moreRead less
Effects Of Nevogenesis Susceptibility Genes And Phenotypic Correlation With Dermoscopic Characteristics Of Nevi
Funder
National Health and Medical Research Council
Funding Amount
$554,099.00
Summary
Melanoma is a form of skin cancer that arises from the cells that produce pigment and is a major public health issue in Australia. We will examine the relationship between the form, structure and colour of existing types of moles and their subsequent risk of developing into melanoma. This will be the first study to combine dermoscopy, a non-invasive examination technique, with DNA tests of the genes that determine skin, hair and eye colour, aiding in the early prediction and diagnosis of skin ca ....Melanoma is a form of skin cancer that arises from the cells that produce pigment and is a major public health issue in Australia. We will examine the relationship between the form, structure and colour of existing types of moles and their subsequent risk of developing into melanoma. This will be the first study to combine dermoscopy, a non-invasive examination technique, with DNA tests of the genes that determine skin, hair and eye colour, aiding in the early prediction and diagnosis of skin cancer.Read moreRead less
Multiple Cytomegalovirus Infections: Biological And Evolutionary Significance.
Funder
National Health and Medical Research Council
Funding Amount
$555,776.00
Summary
This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence ....This project involves the study of cytomegalovirus (CMV) a common viral infection of humans which normally cause little disease. However in individuals whose immune system is suppressed (such as AIDS patients or transplant recipients), or in infection of pregnant women, CMV can cause serious or life-threatening disease in the patient or foetus. An interesting feature of CMV diseases in such patients is that enhanced viral growth and more severe disease is frequently associated with the presence of multiple strains of CMV in the patient. We suggest that mixed CMV infections provide a survival advantage to the virus, with different strains within the mixed infection assisting the growth of other strains. This would result in increased virus growth overall, and enhanced disease. To study the mechanisms by which multiple infections with different CMV strains may affect both the virus and the host, experiments will be performed using an animal model of CMV, murine cytomegalovirus (MCMV). We will examine the effect of the presence of multiple strains of virus on virus growth and distribution within the infected host. We will also determine if functional MCMV strains are capable of assisting non-functional strains to survive within the host. These studies are relevant to the design of a CMV vaccine, and will be valuable in revealing the ways in which viruses can co-operate within an infection.Read moreRead less