The WA Cardiovascular Disease Consortium

The WA Cardiovascular Disease Consortium (WACVDC) was formed in 2003 and comprises all of the extant cardiovascular disease cohort resources in WA that have also collected DNA. Links are currently being formed between each dataset, and all datasets in the consortium not already linked will also be linked to the core WA Data Linkage System. These linkage projects are directly supported by the Western Australian Genetic Epidemiology Resource (WAGER).

Research Objectives

• To link all existing cardiovascular cohort resources in Western Australia (WA) to each other and to the core WA Data Linkage Systems.
• To investigate the life-course genetic epidemiology of cardiovascular disease in population-based datasets from WA.
• To use these linked, population-based resources to:
• Investigate the natural history of cardiovascular disease (CVD).
• Determine the association of genes previously shown to be implicated in the pathogenesis of CVD with clinically relevant parameters across the life-span.
• Investigate the inter-relationships between target genes (epistatic interaction).
• Investigate the inter-relationships between target genes and environmental factors (gene:environment interaction).
• Determine the clinical and public health significance of any positive genetic findings.

Background

Cardiovascular disease (CVD) is a major health and economic burden worldwide. The Australian Institute of Health and Welfare (AIHW) estimates that coronary heart disease will become the major leading public health burden in the world by 2020¹. Within Australia, coronary heart disease and stroke are the first and seconds biggest killers, with 90% of Australian adults having at least one (modifiable) risk factor for heart, stroke and vascular disease, and 25% having three or more¹. While death rates from CVD have declined over the past 30 years, CVD remains one of the leading causes of death in Australia, accounting for 38% of all deaths².

WA Core Data Linkage System

Those countries with the highest chances of success in applying genomic knowledge and tools in clinical and public health settings are those with total population data and family record linkage, so that all those with and without disease can be studied in an unbiased way throughout the whole life span. Such linkages and resources already exist in Western Australia (WA).

We are in the process of developing a national and international resource for genetic epidemiology that will build on the unique WA population health data collected and managed over the last 3 decades. These data are based on linkage within and between the WA statutory collections (all births, deaths, hospitalisations, mental health services contacts, cancer registrations) and additional population disease registers and health surveys ^{3, 4}. These linkages mean that the entire WA population can be monitored for all major diseases/conditions, their risk and protective factors, and the use and role of health services studied. The core datasets now include all birth cohorts since 1980 (including prospective antenatal and perinatal data on all live births in the State); the linkage of hospitalisations and disease registers commenced in the 1970s. Recent additional linkages have commenced to national Medicare and Pharmaceutical Benefits and aged care data from the Health Insurance Commission and Commonwealth Department of Health and Aged Care, enabling the study of all hospital and medical service contacts for particular diseases and conditions. No other state in Australia and very few countries internationally have this capacity, which has been responsible for a large number of epidemiological advances^3,5,6. A number of internationally unique population-based disease registries are linked to the core datasets, e.g., mental health, type-1 diabetes, cerebral palsy, birth defects, and cancer^3-6. Stage 1 of the Family Connections project has recently linked nuclear families within the core WA total-population-based databases back to the early 1970s using electronic registrations, and we are now extending the pedigree linkages back to 1900 using paper records and public assistance (stages 2 and 3).

CVD Research Datasets in WA

As a Consortium, our intent is to build on the information collected (and still being collected) from a number of cohort studies relevant to CVD. All of these populations are of predominantly European (British) origin, and all have had a standard panel of CVD-associated parameters measured (lipid levels, blood pressure, anthropometry, CVD events). Available information for each individual includes clinical history and basic family and racial history. With the exception of Busselton, all of the populations also include detailed CVD physiology (e.g., bilateral carotid ultrasound). All subjects gave written informed consent and all study protocols have been approved by an appropriate Institutional Ethics Committee. In aggregate, these cohorts represent 37,868 consented subjects and 17,193 DNA samples. These clinical and physiological, stored DNA, and long-term follow-up across the life-span provide a unique opportunity to assess the potential impact of genetic polymorphisms on clinical CVD risk.

• The Busselton Health Study
  The Busselton Health Study (BHS) is one of the longest running epidemiological programs in the world. The BHS includes a series of 6 cross-sectional population health surveys of adults (all people listed on the electoral roll) resident in the Shire of Busselton, Western Australia, over the period 1966 to 1981. In 1994/95 all known survivors of these earlier cross-sectional surveys (approx 10,000 people) were invited for a follow-up survey regardless of whether they lived in Busselton or not. The response rate was >50% (n=4,845). Comprehensive sets of demographic, lifestyle, disease, biochemical, haematological and immunological variables were measured in each survey and blood specimens were taken and stored. The 1994/95 survey also collected buffy coat from which DNA has been extracted. A major focus of each survey was the collection of information on conventional cardiovascular risk factors.
• The Carotid Ultrasound Disease Assessment Study (CUDAS)
  The CUDAS group consists of 1,109 subjects with an equal male:female ratio and equal numbers in each age decile between 20 and 70 years8, 9. This population was selected from a random electoral survey from the Perth metropolitan area. Subjects who had previous carotid artery surgery were excluded. A self administered questionnaire has been used to record a history of hypertension, hyperlipidemia, diabetes, angina pectoris, myocardial infarction, stroke or a family history of premature-onset coronary or cerebrovascular disease (by age 55 years) in first degree relatives.
• The Carotid Ultrasound in Patients with Ischaemic Heart Disease (CUPID)
  The CUPID cohort consists of 556 subjects between 26 to 60 years who had angiographically proven coronary artery disease aged 60 years or less at time of angiography. All had a past history of angina, unstable angina or MI and angiographically demonstrated CAD with at least one vessel with >50% stenosis.
• The Raine Study
  The Raine Study seeks to examine the effects of behavioural, environmental and genetic factors contributing to adult cardiovascular disease for 2,000 13 year-old children who have been followed since before birth. Surveys of physical activity, nutrition, psychological and developmental measures, along with cardiovascular and anthropometric measures were taken. Approximately 2,000 DNA samples will be available (by 2005), with relevant information including birth weight, height and weight, BP, and blood results for variable including lipids, triglycerides, HDL and LDL cholesterol.
• The Health-In-Men Study (HIMS)
  The HIMS study assessed aortic diameter and a range of cardiovascular risk factors in 12,203 men aged 65 to 83 years as part of a trial of screening for abdominal aortic aneurysms10. Mortality over the next 3 to 7 years was assessed using record linkage. A sub-study a study of 4,000 men aged between 72 and 87 years old collected additional CVD risk factor surveys and biospecimens (including DNA).
• National Heart Foundation Risk Factor Prevalence Surveys (1980-1999)
  The Australian National Heart Foundation (NHF) has conducted a series of on-going studies of heart disease risk factor prevalence in WA. Studies have been conducted in 1978, 1980, 1983, 1989, 1994 and 1999, with each cross-sectional survey representing an independent, random sample of the WA population. Each study involved a 50:50 male:female ratio of 25-69 year olds, with approximately 1,800 respondents each. Across the six surveys conducted, information on nearly 12,000 respondents is available. DNA was collected from the 1989 (n=800), 1994 (n=1,883) and 1999 (n=2,000) surveys.
• Thrombophilia in Stroke Study (1995-1997)
  Consecutive patients (n=200) were recruited within 7 days of a first-ever stroke admitted to Royal Perth Hospital, together with an equal number of age (+/- 5 years), gender, and post-code matched community controls randomly selected from the electoral roll. Cases have been characterised clinically according to cardiovascular risk factors, type of stroke (ischaemic/haemorrhagic), and presumed aetiologic subtype of ischaemic stroke (large vessel/small vessel/cardioembolic/other). DNA, serum and plasma collected at baseline are stored at minus 80 for all subjects and further serum and plasma samples have been collected in approximately half of stroke patients at 6 months. Blood and DNA samples are available on approximately 150 cases and 150 controls.
• Homocysteine in Stroke Study (1998-ongoing)
  Stroke and TIA patients were recruited, within 7 months of an event, into a randomised Homocysteine in Stroke Substudy of the Vitamins to Prevent Stroke (VITATOPS) Trial (vitatops.highway1.com.au/) . Stroke cases are being characterised clinically according to their demographics (age, gender), cardiovascular risk factors, type of stroke (ischaemic/haemorrhagic), and presumed aetiologic subtype of ischaemic stroke (large vessel/small vessel/cardioembolic/other). All stroke survivors are being followed for clinical outcomes (mean follow up at present is ~3 years). DNA, serum and plasma samples are being collected at baseline and in survivors at 6 months and stored at minus 80. Current recruitment is ~450. Similarly designed sub-studies are currently under way among our VITATOPS collaborators (Chris Chen, Singapore: 500 blood and DNA samples; Reinholdt Schmidt, Austria; Gabriel de Freitis, Rio de Janeiro).
• Perth Vascular Study
  Stroke, coronary, and venous thromboembolism patients are currently being recruited into the Perth Vascular Study (a further cycle of the original Perth Community Stroke Study). Cases are being characterised clinically according to their demographics, cardiovascular risk factors, type of event, medications at the time of the event, and various social data. DNA, serum and plasma are being collected and stored at minus 80. The current recruitment is 120 coronary, 40 stroke and 200 venous thromboembolism patients. Blood and DNA will also be collected from matched community controls (1:1).

Significance of Research

This project will enable the integration of all extant CVD cohort studies available in WA with biospeciman banks and with the WA Data Linkage System. The linkage of the core population-based datasets to a large number of longitudinal cohort studies with extensive exposure data and biospecimens means that we have the potential to investigate the changing roles of genes, environment, gene:gene, and gene:environment interactions in CVD over the entire life span in samples representative of the general Australian population. We anticipate that significant new initiatives and collaborations relevant to gene discovery, clinical and genetic epidemiology, new therapies, preventive medicine, and pharmacogenomics will ensue at the national and international level.

Consortium Members

• Professor Len Arnolda
• Associate Professor John Beilby
• Professor Lawrie Beilin
• Associate Professor Frank van Bockxmeer
• Dr Kim Carter
• Dr Caroline Chapman
• Clinical Professor Graeme Hankey
• Professor Mike Hobbs
• Dr Rae-Chi Huang
• Associate Professor Joe Hung
• Dr Joey Kaye
• Professor Matthew Knuiman
• Dr Kendrick Ling
• Ms Pamela McCaskie
• Dr Brendan McQuillan
• Associate Professor Paul Norman
• Professor Lyle Palmer
• Professor Peter Thompson

References

1. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases: Australian facts 2004. Vol. AIHW Cat no. CVD 27. Canberra: Australian Bureau of Statistics, 2004.
2. Australian Institute of Health and Welfare. Causes of Death in Australia: Australia's health 2002. Vol. ABS Cat no. 4364.0. Canberra: Australian Bureau of Statistics, 2002.
3. Holman CD, Bass AJ, Rouse IL, Hobbs MS. Population-based linkage of health records in Western Australia: development of a health services research linked database. Aust N Z J Public Health 1999; 23:453-9.
4. Croft ML, Read AW, de Klerk N, Hansen J, Kurinczuk JJ. Population based ascertainment of twins and their siblings, born in Western Australia 1980 to 1992, through the construction and validation of a maternally linked database of siblings. Twin Res 2002; 5:317-23.
5. Stanley FJ, Watson L. Methodology of a cerebral palsy register. The Western Australian experience. Neuroepidemiology 1985; 4:146-60.
6. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002; 346:725-30.
7. Welborn T. The Busselton study: mapping population health. Sydney: Australasian Medical Publishing Company, 1998.
8. Chapman CM, Palmer LJ, McQuillan BM, et al. Polymorphisms in the angiotensinogen gene are associated with carotid intimal-medial thickening in females from a community-based population. Atherosclerosis 2001; 159:209-17.
9. Beilby JP, Hunt CC, Palmer LJ, et al. Apolipoprotein E gene polymorphisms are associated with carotid plaque formation but not with intima-media wall thickening: results from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS). Stroke 2003; 34:869-74.
10. Norman P, Le M, Pearce C, Jamrozik K. Infrarenal Aortic Diameter Predicts All-Cause Mortality. Arterioscler Thromb Vasc Biol 2004.