Familial aggregation of albuminuria and arterial hypertension in an Aboriginal Australian community and the contribution of variants in ACE and TP53.

Background: Aboriginal Australians are at high risk of cardiovascular, metabolic and renal diseases, resulting in a marked reduction in life expectancy when compared to the rest of the Australian population. This is partly due to recognized environmental and lifestyle risk factors, but a contribution of genetic susceptibility is also likely.

Methods: Using results from a comprehensive survey of one community (N = 1350 examined individuals), we have tested for familial aggregation of plasma glucose, arterial blood pressure, albuminuria (measured as urinary albumin to creatinine ratio, UACR) and estimated glomerular filtration rate (eGFR), and quantified the contribution of variation at four candidate genes (ACE; TP53; ENOS3; MTHFR).

Relations between markers of renal function, coronary risk factors and the occurrence and severity of coronary artery disease.

Objective: While renal failure greatly increases coronary risk, mild renal impairment is not usually considered a major risk factor. To explore this we assessed relations between measures of mild impairment of renal function and coronary artery disease (CAD) together with other risk factors.

Methods And Results: In 408 consecutive patients aged 75 years or less with angiographically defined normal or obstructed coronary arteries and an estimated glomerular filtration rate (eGFR) >45 mL/min per 1.

Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of L-arginine on its metabolism.

Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase (NOS), has been identified as a new and emerging contributor to, or marker for, cardiovascular risk. The ADMA-mediated regulation of nitric oxide (NO) production is determined by the quantitative bioavailability of intracellular and extracellular ADMA. Dimethylarginine dimethylaminohydrolase (DDAH), which is ubiquitously expressed in tissues, especially liver and kidney, converts the majority of the ADMA to citrulline.

Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.

Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians.

Asymmetric dimethylarginine in homocystinuria due to cystathionine beta-synthase deficiency: relevance of renal function.

Objective: Vascular disease is associated with increased plasma asymmetric dimethylarginine (ADMA) and homocysteine, and both are increased in renal failure. In cystathionine beta-synthase deficiency (CBS) there is severe hyperhomocysteinaemia, precocious vascular disease, and endothelial dysfunction. We investigated whether ADMA levels are elevated in CBS patients with and without renal impairment, and whether lowering plasma homocysteine also lowers ADMA.

Relations between plasma asymmetric dimethylarginine (ADMA) and risk factors for coronary disease.

Background: Elevated plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide production, are reported to be associated with coronary artery disease (CAD).

Methods: We measured plasma levels of ADMA and related compounds, nitrate+nitrite (NO(x)), total homocysteine (tHCY) and assessed renal function and lipid profiles in 145 patients--75 with triple vessel coronary disease and 70 with no detectable coronary disease.

Results: Levels of ADMA, l-arginine, l-arginine/ADMA and plasma NO(x) were not different in the two groups but smokers with triple vessel disease had higher ADMA and lower NO(x) levels than the non-smokers, relationships also present for all smokers and non-smokers in the two groups combined.

Obesity, Type II diabetes and the Ala54Thr polymorphism of fatty acid binding protein 2 in the Tongan population.

Genetic variation of fatty acid binding protein 2 (FABP2) may contribute to the high prevalence of obesity and Type II diabetes in Tonga. To explore this we assessed the frequency of the FABP2 Ala54Thr polymorphism, obesity, and Type II diabetes in Tongans and possible inter-relationships. We investigated 1022 Tongan subjects, 433 men and 589 women aged 15-85 years, to identify possible associations between the FABP2 Ala54Thr polymorphism, obesity, Type II diabetes, BMI, glucose tolerance and standard lipid variables.

A 45-bp insertion/deletion polymorphism of uncoupling protein 2 in relation to obesity in Tongans.

We compared the current prevalence of increased BMI and type 2 diabetes in a representative group of Tongan subjects with measurements made in 1973, and we determined the distribution and possible interrelations with the UCP2 insertion/deletion (ins/del) polymorphism of these variables. We documented the BMI, glucose tolerance, and standard lipid variables in 1012 Tongan subjects (429 men and 583 women, ages 15 to 85 years) during 1998 and 2000 and compared the BMI findings with those of the 1973 survey. We also genotyped for the UCP2 ins/del polymorphism, assessed its association with obesity and type 2 diabetes, and compared its prevalence with those reported for other ethnic populations.

Obesity, Type II diabetes and the beta 2 adrenoceptor gene Gln27Glu polymorphism in the Tongan population.

As there is a high prevalence of obesity in Tonga, we aimed to determine the distribution of the beta2 adrenoceptor gene Gln(27)Glu polymorphism and to assess its relevance to obesity and to Type II diabetes, known to be prevalent in that population. A random sample of 1022 individuals from Tonga were genotyped for the Gln(27)Glu polymorphism in the beta 2 adrenoceptor gene. To assess the prevalence of obesity we measured body-mass index (BMI), fat-free mass, percentage fat and waist-to-hip ratio (WHR).

Homocysteine as a risk factor for cognitive impairment in stroke patients.

Background: Elevated total homocysteine (tHcy) levels are associated with an increased risk of cerebrovascular disease. It is uncertain whether tHcy is also an independent risk factor for cognitive impairment.

Methods: We examined 95 stroke subjects 3 months after their strokes, and 55 healthy comparison subjects, with a detailed neuropsychological assessment, and MRI brain scans in a proportion (n = 97).

Characterization of specifically oxidized apolipoproteins in mildly oxidized high density lipoprotein.

Atherosclerosis is a state of heightened oxidative stress. Oxidized LDL is present in atherosclerotic lesions and used as marker for coronary artery disease, although in human lesions lipids associated with HDL are as oxidized as those of LDL. Here we investigated specific changes occurring to apolipoprotein A-I (apoA-I) and apoA-II, as isolated HDL and human plasma undergo mild, chemically induced oxidation, or autoxidation.

Improved method for plasma malondialdehyde measurement by high-performance liquid chromatography using methyl malondialdehyde as an internal standard.

Measurement of malondialdehyde (MDA) is an important contribution to the assessment of oxidative stress. We report a sensitive and reproducible high-performance liquid chromatography (HPLC) method for measurement of plasma MDA in the assessment of lipid peroxidation. Using methyl malondialdehyde (Me-MDA) as an internal standard with reversed-phase HPLC and UV detection and derivatisation with 2,4 dinitrophenylhydrazine (DNPH), we obtained maximum MDA values with 60-min incubation of 10% plasma with 1 M NaOH at 60 degrees C.

The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment.

Cystathionine beta-synthase (CBS) deficiency is the most common cause of homocystinuria. It is inherited as an autosomal recessive trait and common clinical features are: dislocation of the optic lens, osteoporosis, mental retardation, and thromboembolism. We determined the molecular basis of CBS deficiency in 36 Australian patients from 28 unrelated families, using direct sequencing of the entire coding region of the CBS gene.

Effect of CYP1A1 MspI polymorphism on cigarette smoking related coronary artery disease and diabetes.

CYP1A1, is one of the key detoxifying enzymes catabolizing cigarette smoking derived toxins and may be relevant to smoking-induced atherogenesis. Recently a CYP1A1 MspI polymorphism at the 3'-flanking region of the gene has been found to be associated with smoking related cancer risk and may, therefore, also be associated with vascular disease. To explore this, we investigated interactive effects between smoking and the CYP1A1 MspI polymorphism on coronary artery disease (CAD), diabetes and hypertension in 701 patients (aged < or =65 years) consecutively referred to Eastern Heart Clinic for angiographic investigation.

Glutathione S-transferase mu1 deficiency, cigarette smoking and coronary artery disease.

Background: While genetic variation accounts for a large proportion of interindividual differences in coronary artery disease (CAD) development, environmental factors such as cigarette smoking may genotype-dependently initiate or accelerate the risk. Glutathione S-transferase mu1 (GSTM1) is one of the GST isoenzymes and contributes to the detoxification process of organic compounds produced by cigarette smoking. In the present study we explored the hypothesis that GSTM1 deficiency, caused by GSTM1 null allele, may predispose subjects to cigarette smoking related CAD risk.