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Biomedical subjects

J P Beilby

Publications and source records attributed to J P Beilby.

At least 19 recordsLinked to original sources
PubMed2006

AluyMICB dimorphism within the class I region of the major histocompatibility complex is associated with asthma and airflow obstruction in the Busselton population.

AIM: To examine the association between the Alu dimorphism within the first intron of the MICB gene and asthma and airflow obstruction. Background The highly polymorphic non-classical MHC class I polypeptide-related (MIC) genes, MICA and MICB, encode stress inducible glycoproteins, which are expressed on a variety of epithelial cells, including those of the lungs. METHODS: AluyMICB genotyping was performed on 1109 subjects from the Busselton Health Study. From a standard questionnaire, 359 individuals indicated that they had been diagnosed by a doctor with asthma. Lung function was assessed by the forced expired volume in 1 second (FEV1) and expressed as a percent of the predicted value. Airflow obstruction was defined as FEV1<80% predicted. RESULTS: In men, a dominant relationship was found between the AluyMICB DD genotype and asthma (P=0.006; chi2(2)=7.65). Furthermore, multivariate analysis adjusted for age, height, weight and body mass index (BMI) showed a relationship between DD genotype and asthma in men in a dominant model (odds ratio (OR)=1.97; 95% confidence interval (CI)=1.11-3.51; P=0.021). In women, an association was found between the AluyMICB II genotype and FEV1 percent predicted as a continuous variable (P=0.001). When adjusted for age and BMI, it showed a significant relationship between AluyMICB and airflow obstruction in a dominant model (OR=14.11%, 95% CI 3.29-60.57, P<0.001). However, no association was found between the AluyMICB II genotypes and airflow obstruction in men. CONCLUSION: These findings suggest the possible involvement of a MHC class I gene in abnormal airway structure in women and airway function in men.

Adult↗
PubMed2006

The C-480T hepatic lipase polymorphism is associated with HDL-C but not with risk of coronary heart disease.

High-density lipoprotein cholesterol (HDL-C) is a known predictor of coronary heart disease (CHD). Studies have shown that the C-480T polymorphism of the hepatic lipase (HL) gene is predictive of HDL-C; however, its observed relationship with the risk of CHD has been inconsistent. We analysed four biallelic polymorphisms in the HL gene in participants from three independent Western Australian populations. Samples were collected from two cross-sectional studies of 1111 and 4822 community-based subjects assessed for cardiovascular risk factors, and a third sample of 556 subjects with physician-diagnosed CHD. Genotypes were tested for association with plasma lipids and the risk of CHD. All polymorphisms were highly correlated (D' > 0.97, r(2) > 0.90); therefore, only C-480T was analysed. The -480T allele was significantly associated with an increase in HDL-C of between 0.08 and 0.16 mmol/l in all three populations (p < 0.001). No associations with other lipids were observed, nor was an association with CHD in a case-control study of males. The TT genotype was however associated with decreased risk of myocardial infarction among cases (odds ratio = 0.39, 95% confidence interval = 0.19-0.78, p = 0.008). These findings replicate those of previous studies in three independent populations and suggest that the genetic determinants of CHD are complex and cannot be entirely explained through intermediate phenotypes.

Adult↗
PubMed2001

Polymorphisms in the angiotensinogen gene are associated with carotid intimal-medial thickening in females from a community-based population.

BACKGROUND: Polymorphisms within genes of the renin-angiotensin system have been associated with an increased risk of cardiovascular disease. We investigated the association of polymorphisms in the angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1) genes with increased intima-media thickness (IMT) and the presence of plaques in carotid arteries. METHODS: Subjects (1111) from the Perth Carotid Ultrasound Disease Assessment Study (CUDAS) were genotyped for three polymorphisms: two in the promoter of the AGT gene, G-6A and A-20C; and one in the AGTR1 gene, A1166C. RESULTS: Using multivariate generalised linear models, the AGT-6A allele (P<0.001) and the AGT-20C allele (P<0.03) were significantly associated with increased mean carotid IMT in females but not in males when adjusted for conventional risk factors. The AGTR1 A1166C polymorphism did not show any significant relationship to mean IMT. Results suggest that the I allele of the angiotensin converting enzyme insertion/deletion polymorphism may interact with the AGT-6G allele to increase mean carotid IMT in the population as a whole. None of the polymorphisms investigated were significantly associated with the presence of carotid plaques. CONCLUSION: This study shows that polymorphisms in the angiotensinogen gene are associated with an increased risk of carotid intimal-medial wall thickening in females.

Adult↗
PubMed2001

Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS).

OBJECTIVES: This study examined whether dietary intake or plasma levels of antioxidant vitamins were independently associated with common carotid artery intima-media (wall) thickness (IMT) or focal plaque, or both, in a large, randomly selected community population. BACKGROUND: Oxidation of low-density lipoprotein (LDL) cholesterol is thought to be important in early atherogenesis. Antioxidant micronutrients may therefore protect against lipid peroxidation and atherosclerotic vascular disease. METHODS: We studied 1,111 subjects (558 men and 553 women; age 52 +/- 13 years [mean +/- SD], range 27 to 77). We measured dietary vitamin intake and fasting plasma levels of vitamins A, C and E, lycopene and alpha- and beta-carotene and performed bilateral carotid artery B-mode ultrasound imaging. RESULTS; After adjustment for age and conventional risk factors, there was a progressive decrease in mean IMT, with increasing quartiles of dietary vitamin E intake in men (p = 0.02) and a nonsignificant trend in women (p = 0.10). Dietary vitamin E levels accounted for 1% of the variance in measured IMT in men. For plasma antioxidant vitamins, there was an inverse association between carotid artery mean IMT and plasma lycopene in women (p = 0.047), but not in men. None of the other dietary or plasma antioxidant vitamins, nor antioxidant vitamin supplements, were associated with carotid artery IMT or focal carotid artery plaque. CONCLUSIONS: This study provides limited support for the hypothesis that increased dietary intake of vitamin E and increased plasma lycopene may decrease the risk of atherosclerosis. No benefit was demonstrated for supplemental antioxidant vitamin use.

Antioxidants↗
PubMed2001

A Pro12Ala polymorphism in the human peroxisome proliferator-activated receptor-gamma 2 is associated with combined hyperlipidaemia in obesity.

OBJECTIVE: Peroxisome proliferator-activated receptor-gamma 2 (PPAR gamma 2) is an important regulator of adipose tissue metabolism and insulin sensitivity. The aim of this investigation was to determine whether a PPAR gamma 2 Pro12Ala polymorphism was associated with cardiovascular risk factors (obesity, blood pressure, diabetes and blood lipids) in Western Australian Caucasians (n=663). DESIGN: Subjects were selected from two population studies (the Carotid Ultrasound Disease Assessment Study (CUDAS) and Busselton Population Health Survey) on the basis of body mass index (BMI). 292 obese (BMI > or =30 kg/m) and 371 lean (BMI <25 kg /m) subjects were studied. METHODS: Blood pressure and anthropometric measurements were collected from all participants, as well as a fasting venous blood sample. Biochemical measurements (high-density lipoprotein (HDL)- and low-density lipoprotein-cholesterol, triglycerides) and PPAR gamma 2 Pro12Ala genotype were also determined. RESULTS: Obese Pro/Ala and Ala/Ala subjects had lower levels of HDL-cholesterol (P=0.032) and a trend towards higher levels of triglycerides (P=0.055) compared with obese Pro/Pro subjects. In the obese group, the Ala allele was significantly associated with the presence of combined hyperlipidaemia (odds ratio = 2.33, P=0.042). There was no significant difference in the frequency of the polymorphism between lean and obese groups (P=0.069). No association was observed between Pro12Ala genotype and obesity, blood pressure or diabetes in either group. CONCLUSIONS: Obese carriers of the Pro12Ala polymorphism have a greater risk of developing combined hyperlipidaemia, possibly due to impaired activation of PPAR gamma target genes. The Pro12Ala polymorphism is not directly associated with obesity, hypertension or diabetes in this population.

Aging↗
PubMed2000

Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes.

AIMS: Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes. METHODS: Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero-hepatic recirculation was fitted to group mean serum gliclazide profiles. RESULTS: The Caucasians were older than the Aborigines (mean +/- s.d. age 53.4 +/- 12.2 vs 40.3 +/- 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 +/- 0.4 vs 2.2 +/- 0. 3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model-derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively. CONCLUSIONS: Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect.

Adult↗
PubMed2000

Serum ferritin and C282Y mutation of the hemochromatosis gene as predictors of asymptomatic carotid atherosclerosis in a community population.

BACKGROUND AND PURPOSE: Serum ferritin and heterozygosity for the C282Y mutation of the hemochromatosis gene have both been associated with an increased risk of cardiovascular events. The purpose of the study was to test whether either is a risk predictor for asymptomatic carotid atherosclerosis. METHODS: We assessed carotid intima-media wall thickness (IMT) and focal plaque formation by high-resolution B-mode ultrasound, conventional risk factors, serum ferritin levels, and the C282Y mutation of the hemochromatosis gene in a randomly selected community population of 1098 subjects (545 women and 553 men) aged 27 to 77 years. RESULTS: After adjustment for conventional risk factors, serum ferritin was not associated with carotid mean IMT. Women with ferritin values over the first quartile (>34 microg/L) had an adjusted odds ratio of 2.1 (95% CI, 1. 3 to 3.4; P:=0.0016) for carotid plaque compared with the first quartile. Ferritin was not associated with carotid plaque in men. Subjects who were heterozygous for the C282Y mutation constituted 11. 4% of the population, and there was no independent association of this genotype with either carotid IMT or focal plaque formation. CONCLUSIONS: We conclude that in our community population, C282Y genotype status was not a risk predictor for either carotid mean IMT or plaque formation. Serum ferritin values in women were independently associated with carotid plaque.

Adult↗
PubMed1999

A high-throughput MS-PCR method on MADGE gels for ANG II type-1 receptor A1166C polymorphism.

We have developed a highly accurate, low-cost, single-step, mutagenically separated polymerase chain reaction (MS-PCR) method for the determination of angiotensin II type-1 receptor (AT(1)) A1166C gene polymorphism. The genotypes are determined using the microtiter array diagonal gel electrophoresis (MADGE) system. We have compared the MS-PCR method with allele-specific oligonucleotide hybridization and Dde I digestion techniques for determining the AT(1) A1166C genotype. The combination of MS-PCR and MADGE serves as a model for high-throughput single-nucleotide polymorphism genotyping in large population studies.

Alleles↗
PubMed1999

Hyperhomocysteinemia but not the C677T mutation of methylenetetrahydrofolate reductase is an independent risk determinant of carotid wall thickening. The Perth Carotid Ultrasound Disease Assessment Study (CUDAS)

BACKGROUND: Hyperhomocysteinemia has been identified as a potential risk factor for atherosclerosis. This study examined whether a modest elevation of plasma total homocysteine (tHcy) was an independent risk factor for increased carotid artery intimal-medial wall thickness (IMT) and focal plaque formation in a large, randomly selected community population. We also examined whether vitamin cofactors and the C677T genetic mutation of the methylenetetrahydrofolate reductase (MTHFR) enzyme were major contributors to elevated plasma tHcy and carotid vascular disease. METHODS AND RESULTS: In 1111 subjects (558 men, 553 women) 52+/-13 years old (mean+/-SD; range, 27 to 77 years) recruited from a random electoral roll survey, we measured fasting tHcy and performed bilateral carotid B-mode ultrasound. For the total population, mean tHcy was 12.1+/-4.0 micromol/L. Plasma tHcy levels were correlated with IMT (Spearman rank rs=0.31, P=0.0001). After adjustment for age, sex, and other conventional risk factors, subjects in the highest versus the lowest quartile of tHcy had an odds ratio of 2.60 (95% CI, 1.51 to 4.45) for increased IMT and 1.76 (95% CI, 1.10 to 2.82) for plaque. Serum and dietary folate levels and the C677T mutation in MTHFR were independent determinants of tHcy (all P=0.0001). The mutant homozygotes (10% of the population) had higher mean tHcy than heterozygotes or those without the mutation (14.2 versus 12.3 versus 11.6 micromol/L, respectively, P=0.0001). The inverse association of folate levels with tHcy was steeper in the mutant homozygotes. Despite this, the C677T MTHFR mutation was not independently predictive of increased carotid IMT or plaque formation. CONCLUSIONS: Mild hyperhomocysteinemia is an independent risk factor for increased carotid artery wall thickness and plaque formation in a general population. Lower levels of dietary folate intake and the C677T mutation in MTHFR are important causes of mild hyperhomocysteinemia and may therefore contribute to vascular disease in the community.

Adult↗
PubMed1999

Genotyping as a diagnostic aid in genetic haemochromatosis.

BACKGROUND: Two mutations in a newly described gene, HFE, have been proposed as genetic markers for the inherited iron overload disease, genetic haemochromatosis. METHODS: We assessed the frequency of both mutations in a cohort of genetic haemochromatosis patients and compared these with a control population. The patients were genetic haemochromatosis patients from Western Australia whose diagnosis met strict criteria for phenotypic expression. Control patients had other liver disease where iron overload was excluded. RESULTS: Genomic DNA of 72 genetic haemochromatosis patients and 69 controls was examined for the C282Y and H63D mutations of the HFE gene using polymerase chain reaction amplification and restriction enzyme digestion. In genetic haemochromatosis patients, the C282Y mutation was homozygous in 64 of 72, giving a sensitivity of 89% (95% confidence interval 82-96%), heterozygous in five (7%) and absent in another three (4%), whereas none of the control subjects were homozygous. The H63D mutation was present in one genetic haemochromatosis patient and was not useful as a diagnostic marker. In this cohort of Western Australian patients with phenotypic expression of genetic haemochromatosis, the specificity of a homozygous C282Y mutation for genetic haemochromatosis was 100%. CONCLUSIONS: The results indicate that genotyping for the C282Y mutation is a useful test for the diagnosis of genetic haemochromatosis in clinical practice.

Amino Acid Substitution↗
PubMed1999

Angiotensin-converting enzyme gene polymorphism and carotid wall thickening in a community population.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of coronary heart disease, but whether it is a risk factor for underlying atherosclerosis remains unclear. Therefore, we examined to see whether the ACE gene deletion polymorphism was associated with carotid wall thickening and atherosclerotic plaque formation in a large randomly selected community population. A total of 1111 subjects, aged 27 to 77 years, with an equal male:female ratio and equal numbers in each age decile, were randomly selected from the Perth community population. Mean common carotid intima-medial wall thickness (IMT) and focal plaque formation were assessed by high-resolution B-mode ultrasound. The ACE gene I/D polymorphism was detected by PCR. The distribution of the ACE genotypes conformed to the Hardy-Weinberg equilibrium (DD, 31.0%; ID, 48.4%; and II, 20.6%). The D allele was strongly correlated in a codominant fashion with plasma ACE activity (r(s)=0.53, P<0.0001), and accounted for 33% of the total variance in circulating ACE activity. No significant differences among the ACE genotypes were found with respect to age, sex, and conventional risk variables, including a history of hypertension and vascular disease. The average mean IMT and prevalence of increased IMT and focal plaque were not significantly different among genotypes in the overall population or in the subset (n=852) who were conventionally low risk by Framingham coronary heart disease risk score. Logistic regression analysis selected age, systolic blood pressure, pack-years of smoking, LDL cholesterol level, waist/hip ratio, and history of hypertension, but not the D allele, as multivariate predictors of increased IMT and carotid plaque formation. We conclude that, although the ACE I/D polymorphism is strongly related to ACE activity, it is not a risk predictor of carotid wall thickening or focal plaque formation when examined in a large randomly selected community population.

Adult↗
PubMed1999

Biological variability and reference intervals for total plasma homocysteine.

We determined the intra-individual biological variability of plasma homocysteine in 20 healthy subjects. The intra-individual coefficient of variation was relatively low (8.3%), indicating that a single measurement can be used to characterize the average homocysteine concentration. A population study measuring plasma homocysteine and serum folate levels was conducted on serum samples collected from 1109 randomly selected, fasting adults with a wide age range. We determined age- and gender-specific central 0.95 intervals and found that subjects in the highest quartile of serum folate had significantly lower (P = 0.0001) mean plasma homocysteine concentrations than did those in the lowest quartile of folate values. An 'ideal' homocysteine reference range, based on targeting those subjects who are likely to be folate replete, is preferable to the population-based range using the central 0.95 interval.

Adult↗
PubMed1998

Carbohydrate-deficient transferrin as a marker of change in alcohol intake in men drinking 20 to 60 g of alcohol per day.

We evaluated carbohydrate-deficient transferrin (CDT) and gamma-glutamyltranspeptidase (gamma-GT) as markers of alcohol intake and change in alcohol intake in white Australian men aged 20 to 63 years who regularly drank 20 to 60 g of alcohol/day (2 to 6 standard drinks), either as weekend (n = 14) or daily drinkers (n = 41). After 4 weeks of familiarization on usual alcohol intake, men were provided with low alcohol beer (24 x 375 ml cans, 0.9%, v/v, two-weekly), and, for 4 weeks, consumed as much or as little as they wished with no additional alcohol permitted. In an alternate 4-week period, the same amount of full-strength beer (4.9%, v/v) was provided, whereas subjects continued their usual amount and pattern of alcohol consumption. The order of experimental conditions was randomized. Retrospective 7-day diaries documented weekly alcohol intake during 4 weeks of familiarization and 8 weeks of intervention. Mean alcohol intake was 345 g/week of alcohol (SD 97) during familiarization. During the last 4 weeks of intervention (study weeks 8 to 12), mean alcohol intake either increased by 360 g/week (SD 138) with the switch from low to high alcohol or decreased by 328 g/week (SD 120) with the reverse. During familiarization (study weeks 1 to 4), alcohol intake was significantly related independently (R2 = 0.21) to mean corpuscular volume (p = 0.008) and uric acid (p = 0.003), but not to gamma-GT (p = 0.22) nor CDT (p = 0.94). Change in alcohol intake was predicted independently (R2 = 0.60) by change in CDT (p < 0.0001) and gamma-GT (p = 0.0003), but not by change in uric acid or mean corpuscular volume. A 10% change in CDT gave 70% sensitivity and 80% specificity to detect a change of at least 2 standard drinks/day; respective values were 68% and 0 for 10% change in gamma-GT. Results were not related to drinking pattern, smoking, age, or weight. CDT, particularly when used as a continuous variable, may have a place in monitoring alcohol consumption, even in men whose alcohol intake is in the 20 to 60 g/day range.

Adult↗
PubMed1997

Cardiac troponin I should replace CKMB for the diagnosis of acute myocardial infarction.

Cardiac troponin I (cTnI) has been reported to be a highly specific marker for cardiac injury. We investigated the performance of this assay in patients admitted to a coronary care unit for suspected acute myocardial infarction (AMI), patients with extensive skeletal muscle damage, marathon runners and as a routine diagnostic test over a four week period. cTnI proved to be as sensitive a marker for AMI as creatine kinase/MB isoenzyme (CKMB) in patients admitted to the coronary care unit. In 10 patients with a proven AMI, the cTnI remained elevated from 69 to 183 h with a median time of 127 h. Cardiac troponin I had superior specificity to CKMB in patients with skeletal muscle damage. It was very useful in these patients to confirm or exclude concurrent myocardial damage. In routine diagnostic use, cTnI had greater efficiency than CKMB to classify patients as having an AMI. Consequently cTnI should replace CKMB as a marker for AMI.

Coronary Care Units↗