Group Leader: David Wilcken

Overview:

The Cardiovascular genetics group is clinically orientated and liaises actively with clinicians and biochemical colleagues in collaborative studies. Genes and lifestyle factors (environment) each contribute about 50% to the occurrence and severity of vascular disease, particularly coronary disease, the major cause of adult death and disability in developed countries. Our group aims to explore selective aspects of these in Caucasian and non-Caucasian populations.

Projects:

Hyperhomocysteinaemia and Vascular Disease
Markedly elevated circulating levels of the amino acid homocysteine occurs in the inborn error of metabolism homocystinuria, a disorder in which 50% of untreated patients suffer a vascular event before the age of thirty years. Mette Gaustadnes has identified the genotypes responsible for this recessively inherited disorder in our Australian patients and related genetic variability to response to, or resistance to, treatment. In a separate trans-national study of this disorder with colleagues in London, Manchester, Dublin and Holland we have established that treatment to aggressively lower the elevated homocysteine dramatically reduces cardiovascular risk.

There's evidence that mild homocysteine elevation which occurs in about 20% of coronary patients is associated with enhanced vascular risk. In a recent collaborative study we have established that very small increases in oral folic acid, just 0.2mg per day which could be obtained with an appropriate diet, reduces plasma homocysteine by 2/3 of that obtained with a standard 2mg dose, emphasising the importance of dietary folic acid. The effect of pharmacological folate doses on cardiovascular risk is currently being explored in large case-control studies worldwide.

Non-Caucasian population studies
In a study of over 1000 Tongan subjects in association with the hospital's Diabetes group (Professor Stephen Colagiuri) Natalia Duarte has identified a uniquely high (97%) homozygosity for an uncoupling protein 2 (UCP2) gene variant in association with a high prevalence of Type II diabetes and obesity in that population. This may represent a founder effect.

In a study of Aboriginal Australians in association with the Menzies School of Health in Darwin we identified a highly significant association between a gene variant of the short-lived nuclear protein p53 and albuminuria, and a marker of renal disease. The genotype was also associated with increasing degrees of glucose intolerance. These results are indicative of a population specific genetic and environmental interaction.

Group members:

Key Publications:

1. Wilcken DEL. Overview of inherited metabolic disorders causing cardiovascular disease. Journal of Inherited Metabolic Disease 2003; 26(2-3): 245-257

2. Duarte NL Colaguiri S, Palu T, Wang XL, Wilcken DEL. Obesity, TypeII diabetes and the Ala54Thr polymorphism of fatty acid binding protein in the Tongan population. Mol Genet Metab. 2003 Jul; 79(3): 183-8

3. Duarte NL Colaguiri S, Palu T, Wang XL, Wilcken DEL. A 45-bp insertion/deletion polymorphism of uncoupling protein 2 in relation to obesity in Tongans. Obs. Res. 2003 Apr; 11(4): 512-7

4. Wilcken DEL. Clinical Physiology of the Normal Heart. In:The Oxford Textbook of Medicine,4th edition 2003, Warrell D, Cox T, Firth J, eds. Oxford University Press, volume 2, pp 820 - 828.

5. Chan DKY, Lam MKP, Wong R, Hung WT, Wilcken DEL. Strong association between
N-acetyltransferase 2 genotype and Parkinson's Disease in Hong Kong Chinese. Neurology 2003 Mar 25; 60(6): 1002-5.

6. Duarte NL, Colagiuri S, Palu T, Wang XL, Wilcken DEL. Obesity, Type II diabetes and the beta 2 adrenoceptor gene Gln27Glu polymorphism in the Tongan population. Clinical Science(Lond). 2003 Mar; 104(3): 211-5

7. Sachdev PS, Valenzuela MJ, Brodaty H, Wand XL, Looi J, Lorentz L Howard L, Jones M, Zagami AS, Gillies D. Wilcken DEL. Homocyseine is a risk factor for cognitive impairment in stroke patients. Demen Geriatr Cogn Disord. 2003;15(3):155-62

8. Pankhurst G, Wang XL, Wilcken DEL, Baernthaler G, Panzenbock U, Raftery M, Stocker R. Characterization of specifically oxidized apolipoproteins in mildly oxidised high densitity lipoprotein. J Lipid Res. 2003 Feb;44(2):349-55

9. Sim AS, Salonikas C, Naidoo D, Wilcken DEL. Improved method for plasma malondialdehyde measurement by high-performance liquid chromatography using methyl malondialdehyde as an internal standard. Journal of Chromatography B Analyt Technol Biomed Life Science 2003 Mar 5; 785(2): 337 - 44.

10. Wang XL, Greco M, Sim AS, Duarte N, Wang J, Wilcken DE.
Effect of CYP1A1 MspI polymorphism on cigarette smoking related coronary artery disease and diabetes. Atherosclerosis. 2002; 162(2): 391-7.

11. Neal B, MacMahon S, Ohkubo T, Tonkin A, Wilcken D.
Dose-dependent effects of folic acid on plasma homocysteine in a randomized trial conducted among 723 individuals with coronary heart disease. Eur Heart J. 2002; 23(19): 1509-15.

12. McDonald SP, Hoy WE, Maguire GP, Duarte NL, Wilcken DE, Wang XL.
The p53Pro72Arg polymorphism is associated with albuminuria among aboriginal Australians. J Am Soc Nephrol. 2002; 13(3): 677-83.

13. Gaustadnes M, Wilcken B, Oliveriusova J, McGill J, Fletcher J, Kraus JP, Wilcken DE.
The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutat. 2002; 20(2): 117-26.

14. Yap S, Boers GH, Wilcken B, Wilcken DE, Brenton DP, Lee PJ, Walter JH, Howard PM, Naughten ER.
Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol. 2001; 21(12): 2080-5.

Funding sources:

Eastern Heart Clinic
The PACIFIC Clinical Trial
Royal Prince Alfred Heart Research Institute
Government of Denmark Scholarship (Dr. Mette Gaustadnes)
Centre for Thrombosis and Vascular Research
New South Wales Government Research Grant.