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Biomedical subjects

A J Hanley

Publications and source records attributed to A J Hanley.

At least 19 recordsLinked to original sources
PubMed2003

Relation of waist circumference and glycemic status to C-reactive protein in the Sandy Lake Oji-Cree.

OBJECTIVE: To determine the prevalence of elevated C-reactive protein (CRP) in the Sandy Lake Oji-Cree, an aboriginal community residing in the Sioux Lookout zone of Northwestern Ontario, Canada, and to determine the associations of obesity and diabetes with CRP in a community with a very high prevalence of type II diabetes. DESIGN: We surveyed 512 community members aged 18 y and older to determine the prevalence and the determinants of elevated CRP in Sandy Lake. MEASUREMENTS: Clinical variables, indices of obesity and serum concentrations of CRP, insulin, serum amyloid A (SAA) and interleukin-6 (IL-6). RESULTS: The prevalence of CRP >or=3.8 mg/l was significantly higher in women than in men (51% vs. 32%, P<0.0001). Regression analysis determined that body mass index and IL-6 were independent determinants of CRP concentration in women and waist circumference and IL-6 were independent determinants of CRP concentration in men. Diabetes was associated with elevated CRP in both sexes, but was only a moderate strong determinant in CRP concentration in multivariate regression analysis. CONCLUSIONS: The prevalence of elevated CRP in this aboriginal community is remarkably high. These data further demonstrate that the association between CRP and specific indices of obesity and metabolism vary according to gender and glycemic status.

Adolescent↗
PubMed2001

Physical activity, anthropometric factors and risk of pancreatic cancer: results from the Canadian enhanced cancer surveillance system.

To explore the hypothesis that insulin resistance may be an etiologic factor in pancreatic cancer, we assessed the pancreatic cancer risk associated with anthropometric factors and physical activity, both of which are important determinants of insulin sensitivity in humans. Three hundred and twelve patients with histologically confirmed pancreatic cancer were compared to 2,919 controls in a population-based, case-control study in 7 of the 10 Canadian provinces. Participants were asked to report their exposure status for the period 2 years before interview. Men in the highest quartile of body mass index (BMI, > or =28.3 kg/m(2)) were at increased risk of pancreatic cancer [adjusted odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.08-3.35]. In addition, men who reported a decrease in weight of at least 2.9% from their lifetime maximum were at reduced risk compared to those reporting a < or =2.9% loss (> or =10.2% loss, OR = 0.51, 95% CI 0.30-0.86). BMI 2 years before interview was not associated with pancreatic cancer risk among women, though those reporting a > or =12.5% decrease in weight from their lifetime maximum had substantially lower risk compared to those in the baseline quartile (OR = 0.53, 95% CI 0.29-0.99). After adjustment for age, province of residence, dietary intake and anthropometric factors, men in the highest quartile of the composite moderate and strenuous physical activity index were at reduced risk of pancreatic cancer (OR = 0.53, 95% CI 0.31-0.90). Physical activity did not appear to be associated with pancreatic cancer among women, though a tendency for reduced risk with increasing levels of strenuous activity was suggested (p for trend = 0.06). Our findings support the hypothesis that insulin resistance is an etiologic factor in the development of pancreatic neoplasms among men and possibly women.

Age Factors↗
PubMed2001

Variable association between genetic variation in the CYP7 gene promoter and plasma lipoproteins in three Canadian populations.

The promoter sequence variant -278A in the CYP7 gene, which encodes cholesterol 7-alpha hydroxylase, was previously reported to be associated with reduced plasma low density lipoprotein (LDL) cholesterol concentration. We tested for association of CYP7-278A with plasma lipoprotein traits in samples taken from three distinct Canadian populations: 594 Alberta Hutterites, 325 Ontario Oji-Cree and 190 Keewatin Inuit. The CYP7-278A allele frequencies in these three groups were 0.708, 0.466 and 0.490, respectively. The frequencies of CYP7-278A/A homozygotes were 0.481, 0.215 and 0.247, respectively. In the Hutterites, CYP7-278A was associated with reduced plasma HDL-cholesterol and apolipoprotein AI concentration. In the Oji-Cree, CYP7-278A was not significantly associated with any plasma lipoprotein trait. In the Inuit CYP7-278A was associated with elevated plasma total and LDL-cholesterol. There was no consistent relationship between the population mean plasma LDL-cholesterol concentration and the population CYP7-278A frequency. Our findings suggest that the common -278A promoter variant of CYP7 was inconsistently associated with variation in plasma LDL- and HDL-cholesterol in samples from three independent populations. The inconsistencies could be due to differences in genetic background or to unspecified environmental or genetic factors.

Adult↗
PubMed2001

Association of a single nucleotide polymorphism in CPB2 encoding the thrombin-activable fibrinolysis inhibitor (TAF1) with blood pressure.

Thrombin-activable fibrinolysis inhibitor (TAFI) is a hepatically secreted zymogen, whose substrates include bradykinin. The CPB2 gene encoding TAFI is a candidate gene for blood pressure. A recently identified single nucleotide polymorphism (SNP) in the CPB2 coding region, designated as 1057C > T, results in an amino acid change at TAFI residue 325 (Ile > Thr325). We found that the genotype based on this SNP was significantly associated with blood pressure in aboriginal Canadians. Specifically, analysis of variance showed that homozygotes for CPB2 1057T had significantly lower diastolic blood pressure than subjects with other CPB2 genotypes. CPB2 genotype accounted for approximately 3% of the total variation in diastolic blood pressure. consistent with the expected magnitude of a modest genetic effect in a complex trait such as blood pressure. Although the mechanism underlying the association is unclear, the findings are of interest because TAFI may provide a link between coagulation and blood pressure regulation.

Adolescent↗
PubMed2001

Physical activity, physical fitness, and insulin and glucose concentrations in an isolated Native Canadian population experiencing rapid lifestyle change.

OBJECTIVE: Little is known about the relation of physical activity and physical fitness to insulin resistance and glucose intolerance in isolated subarctic Native Canadian populations. The purpose of this effort was to examine the relation between activity and fitness and obesity and glucose concentrations in such a unique population. RESEARCH DESIGN AND METHODS: This study describes 530 men and women from the community of Sandy Lake, Ontario, located in the boreal forest region of central Canada. Fasting blood glucose and insulin concentrations were determined after an overnight fast. Past year physical activity levels were assessed using a modified version of an interviewer-administered questionnaire. Maximal oxygen uptake, a measure of cardiovascular fitness, was estimated using a submaximal step test. RESULTS: Total (leisure and occupational) physical activity and physical fitness were significantly associated with fasting insulin concentrations after adjusting for age, BMI or percent body fat, waist circumference, and fasting glucose concentration in men but not in women. The relations between physical activity, fitness, and fasting glucose concentrations were not as strong or as consistent as they were when fasting insulin concentration was the dependent variable. CONCLUSIONS: In this isolated Native Canadian community, both physical activity and fitness were independently associated with fasting insulin concentrations, suggesting a beneficial role of physical activity/fitness on insulin sensitivity that is separate from any influence of activity on body composition. The fact that this relation was found in men but not in women is most likely explained by issues related to the measurement of activity and fitness in this study and the fact that the women in this population appear to be less active than the men.

Adolescent↗
PubMed2001

Cross-sectional and prospective associations between proinsulin and cardiovascular disease risk factors in a population experiencing rapid cultural transition.

OBJECTIVE: To examine cross-sectional and prospective associations between proinsulin and cardiovascular disease risk factors using data from a population-based study of type 2 diabetes among Native Canadians. RESEARCH DESIGN AND METHODS: Between 1993 and 1995, 72% of eligible members of a Native Canadian community participated in a baseline diabetes prevalence survey. Fasting samples were collected for glucose, C-peptide, proinsulin, lipids, and apolipoproteins. A 75-g oral glucose tolerance test was administered, and a second sample for glucose was drawn after 120 min. Blood pressure and waist circumference were determined. In the present study, subjects with normal glucose tolerance (NGT) (n = 505) and impaired glucose tolerance (IGT) (n = 74) were included in cross-sectional analyses. In 1998, 95 individuals who had IGT or NGT at baseline with an elevated 2-h glucose concentration (> or = 7.0 mmol/l) participated in a follow-up evaluation using the protocol used at baseline. Cross-sectional and prospective associations between proinsulin and cardiovascular risk factors were assessed using correlation and multiple linear regression analyses. RESULTS: After adjustment for covariates including age, sex, C-peptide, waist circumference, and glucose tolerance status, fasting proinsulin concentration was significantly associated with concurrently measured lipid and apolipoprotein concentrations (triglycerides: r = 0.18, P < 0.0001; total cholesterol: r = 0.10, P = 0.02; LDL cholesterol: r = 0.11, P = 0.01; HDL cholesterol: r = -0.16, P = 0.0002; apolipoprotein (apo) B: r = 0.17, P < 0.0001; apoAI: r = -0.11, P = 0.008). In the adjusted prospective analysis, baseline triglycerides, HDL cholesterol, and apoB were associated with changes over time in proinsulin (r = 0.23, P = 0.04; r = -0.30, P = 0.01; r = 0.23, P = 0.04; respectively). CONCLUSIONS: These results confirm previously reported cross-sectional associations between proinsulin and lipid concentrations. In addition, an unexpected association between baseline lipids and proinsulin change was documented.

Adult↗
PubMed2000

The efficacy of stethoscope placement when not in use: traditional versus "cool".

OBJECTIVE: To determine whether the "cool" or circumcervical placement of the stethoscope when not in use is as efficacious as the traditional placement in terms of transfer time to the functional position. METHODS: Measurement of time taken by 100 health care professionals in each group to transfer stethoscope to functional position. RESULTS AND INTERPRETATION: The cool group was much slower than the traditional group, despite their younger years. This wasted time could translate into a substantial financial burden on Canada's health care system.

Humans↗
PubMed2000

Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians.

We previously showed that a rare mutation in LMNA, which encodes lamins A and C, underlies autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). Because FPLD is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes. We therefore analyzed the relationships between the common LMNA 1908T/C single nucleotide polymorphism (SNP) and plasma leptin and anthropometric indices in 306 nondiabetic Canadian Oji-Cree. We found that subjects with the LMNA 1908T/1908T genotype had significantly higher plasma leptin than the subjects with either the 1908C/1908T or 1908C/1908C genotypes, after adjustment for age and sex. Physical indices of obesity, such as body mass index, percent body fat, and ratio of waist-to-hip circumference, were also higher among Oji-Cree subjects with the LMNA 1908T/1908T genotype than the subjects with either the 1908C/1908T or 1908C/1908C genotypes. The results suggest that common genetic variation in LMNA may be an important determinant of plasma leptin and obesity-related quantitative traits.

Adult↗
PubMed2000

"Hypotyrosinemia" in phenylketonuria.

It has been postulated that the significant incidence of learning disabilities in well-treated patients with phenylketonuria (PKU) may be due, in part, to reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membrane. Hypotyrosinemia has been reported in treated and untreated PKU but virtually no data are available. We decided to examine this in our patient population and to compare it with the published norms, patient data from our hospital clinical biochemical laboratory database, and a group of normal children and adolescents in a private pediatric practice. We found that the mean nonfasting plasma tyrosine in 99 classical PKU patients was 41.1 micromol/L, in 26 mild (atypical) PKU patients 53.3 micromol/L, and in 35 non-PKU mild hyperphenylalaninemia patients 66.6 micromol/L. This compared to nonfasting plasma tyrosine levels in 102 non-PKU subjects of 64.0 micromol/L in our hospital biochemistry database, 69.1 micromol/L in 58 volunteers in the private office practice, and 64-78.8 micromol/L in infants, children, and adolescents in the literature review. Our data support the previously undocumented statements in the literature that plasma tyrosine levels are low in PKU.

Adolescent↗
PubMed2000

Disparity between association and linkage analysis for HNF1A G319S in type 2 diabetes in Canadian Oji-Cree.

In parallel experiments designed to find the genetic determinants of type 2 diabetes in Oji-Cree, we identified several linked chromosomal regions, using genomic scanning, in addition to a private diabetes-associated mutation, namely HNF1A G319S, using candidate gene sequencing. The genome scan did not identify the region harboring HNF1A as being linked with diabetes. Also, the HNF1A mutation, when used directly in sib-pair linkage analysis, was not linked with diabetes. However, HNF1A G319S was very strongly associated with diabetes, predicted the clinical severity of diabetes, and performed well as a diagnostic predictive test for diabetes in the Oji-Cree. Despite the failure of linkage analysis to identify HNF1A as a determinant of type 2 diabetes, we feel justified in interpreting that G319S has a very important pathogenic role in Oji-Cree diabetes, based upon the highly suggestive association studies. The probable etiologic heterogeneity of type 2 diabetes in the Oji-Cree created a situation in which association analysis was much more sensitive to detect a relationship between HNF1A S319 and diabetes than was linkage analysis. The effectiveness of linkage analysis will probably be limited in study samples that have an even greater complexity of genetic background and/or disease etiology. Thus, the absence of linkage does not always mean that a genomic variant is not an important determinant of a complex disease. Furthermore, our experience confirms the value of using several complementary strategies to identify susceptibility genes for a complex disease.

Alleles↗
PubMed2000

Gender, obesity, hepatic nuclear factor-1alpha G319S and the age-of-onset of type 2 diabetes in Canadian Oji-Cree.

Among the Oji-Cree of northern Ontario, women have both a higher prevalence and an earlier onset of type 2 diabetes compared to men. We studied the relationship between HNF1A S319 and both the presence of and the age-of-onset of type 2 diabetes in women and men separately. We found that: 1) in women, there was a significant difference in the mean age-of-onset of type 2 diabetes according to HNF1A genotype; and 2) in men, there was no difference in the mean age-of-onset of type 2 diabetes according to HNF1A genotype. The findings indicate that HNF1A S319 is associated with increased susceptibility to type 2 diabetes in both men and women, but with earlier age-of-onset in women only. One factor that might account for the gender difference in the onset of HNF1A S319-associated type 2 diabetes is the greater prevalence and severity, and earlier onset of, obesity among female Oji-Cree.

Adolescent↗
PubMed2000

Overweight among children and adolescents in a Native Canadian community: prevalence and associated factors.

BACKGROUND: The prevalence of pediatric obesity in North America is increasing. Native American children are at especially high risk. OBJECTIVES: The objective was to evaluate the prevalence of pediatric overweight and associated behavioral factors in a Native Canadian community with high rates of adult obesity and type 2 diabetes mellitus. DESIGN: Height and weight were measured in 445 children and adolescents aged 2-19 y. Fitness level, television viewing, body image concepts, and dietary intake were assessed in 242 subjects aged 10-19 y. Overweight was defined as a body mass index > or =85th percentile value for age- and sex-specific reference data from the third National Health and Nutrition Examination Survey (NHANES III). Multiple logistic regression was used to examine factors associated with overweight, with adjustment for age and sex. RESULTS: The overall prevalence of overweight in subjects aged 2-19 y was significantly higher than NHANES III reference data [boys: 27. 7% (95% CI: 21.8, 34.5); girls: 33.7% (95% CI: 27.9, 40.1)]. In the subset aged 10-19 y, > or =5 h television viewing/d was associated with a significantly higher risk of overweight than was < or =2 h/d [odds ratio (OR) = 2.52; 95% CI: 1.06, 5.98]. Subjects in the third and fourth quartiles of fitness had a substantially lower risk of overweight than did those in the first quartile [third quartile compared with first quartile: OR = 0.24 (95% CI: 0.09, 0.66); fourth quartile compared with first quartile: OR = 0.13 (95% CI: 0.03, 0. 48)]. Fiber consumption on the previous day was associated with a decreased risk of overweight (OR = 0.69; 95% CI: 0.47, 0.99 for each 0.77 g/MJ increase in fiber intake). CONCLUSIONS: Pediatric overweight is a harbinger of future diabetes risk and indicates a need for programs targeting primary prevention of obesity in children and adolescents.

Adolescent↗
PubMed2000

Alcohol, tobacco and coffee consumption and the risk of pancreatic cancer: results from the Canadian Enhanced Surveillance System case-control project. Canadian Cancer Registries Epidemiology Research Group.

The relationship between alcohol, tobacco and coffee consumption and pancreatic cancer was investigated using population-based case-control data obtained from eight Canadian provinces. Our findings are based on analyses performed on 583 histologically confirmed pancreatic cancer cases and 4813 controls. Questionnaire data were obtained directly from 76% of the cases. Male subjects with 35 or more cigarette pack-years had an increased risk of developing pancreatic cancer relative to never smokers (OR= 1.46, 95% CI 1.00-2.14). Similarly, women reporting at least 23 cigarette pack-years of smoking had an odds ratio of 1.84 (95% CI 1.25-2.69). For the most part, consumption of total alcohol, wine, liquor and beer was not associated with pancreatic cancer. Coffee drinking was not related to pancreatic cancer. More work is needed to clarify the role of these and other potentially modifiable risk factors as a means to reduce the incidence of this disease for which treatment results remain disappointing.

Adult↗
PubMed2000

NAT2 polymorphism associated with plasma glucose concentration in Canadian Oji-Cree.

The prevalence of type 2 diabetes in the Oji-Cree of Northern Ontario is among the highest of any population in the world. We previously demonstrated that markers D8S264 and D22S683 were both linked and associated with type 2 diabetes in the Oji-Cree. Among the possible candidate genes for type 2 diabetes and related traits on chromosomes 8p and 22q were NAT2 and CYP2D6, respectively. We thus explored the possible association of NAT2 and CYP2D6 alleles and diabetes-related traits in a sample of 112 Oji-Cree subjects with type 2 diabetes and 481 Oji-Cree subjects without type 2 diabetes. We found no difference in the allele and genotype frequencies of the NAT2 G191A, C282T, C481T, G590A, A803G and G857A, and the CYP2D6 G1934A polymorphisms between Oji-Cree subjects with and without type 2 diabetes. However, we found a significant association between the NAT2 C282T polymorphism and plasma fasting glucose concentration. Specifically, NAT2 282T/T homozygotes had significantly higher plasma fasting glucose than 282C/C homozygotes, and heterozygotes had intermediate levels of this trait. Thus, variation in NAT2 or CYP2D6 was not associated with the presence of type 2 diabetes, and would not be causative for this phenotype in Oji-Cree. However, NAT2 might be a 'modifier gene' affecting the level of glycaemia in non-diabetic subjects.

Adolescent↗
PubMed2000

The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree.

We previously showed an extremely strong association between type 2 diabetes and a private polymorphism, namely G319S, in the hepatocyte nuclear transcription factor (HNF)-1alpha. Because HNF-1alpha is involved in the transcription of several apolipoprotein genes, we tested for an association between the private HNF1A G319S variant and plasma lipoproteins in a sample of 55 unrelated Oji-Cree subjects with type 2 diabetes and 175 unrelated Oji-Cree subjects without type 2 diabetes. In Oji-Cree subjects with type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with lower plasma concentrations of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein (apo) B. In Oji-Cree subjects without type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with higher plasma concentrations of high density lipoprotein cholesterol and apo AI. There were no associations with plasma triglycerides or lipoprotein(a). Regression analysis indicated that the HNF1A genotype accounted for approximately 10% of the variation in the apo B-related traits in the diabetic subjects and for approximately 5% of the variation in the apo AI-related traits in the nondiabetic subjects. Furthermore, the regression model indicated that the HNF1A S319 allele affected these traits in a dominant manner in subjects with and without type 2 diabetes. These findings provide the first evidence that a rare variant in a nuclear transcription factor is associated with variation in plasma lipoprotein traits.

Adolescent↗
PubMed2000

Common and rare ABCA1 variants affecting plasma HDL cholesterol.

Mutations in ABCA1, a member of the ATP-binding cassette family, have been shown to underlie Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA), which are genetic disorders that are characterized by depressed concentrations of plasma high density lipoprotein (HDL) cholesterol. An important question is whether common variants within the coding sequence of ABCA1 can affect plasma HDL cholesterol in the general population. To address this issue, we developed a screening strategy to find common ABCA1 variants. This strategy involved long-range amplification of genomic DNA by using coding sequences only, followed by deep sequencing into the introns. This method helped us to characterize a new set of amplification primers, which permitted amplification of virtually all of the coding sequence of ABCA1 and its intron-exon boundaries with a single DNA amplification program. With these new sequencing primers, we found 3 novel ABCA1 mutations: a frameshift mutation (4570insA, A1484S-->X1492), a missense mutation (A986D) in a TD family, and a missense mutation (R170C) in aboriginal subjects with FHA. We also used these sequencing primers to characterize 4 novel common amino acid variants in ABCA1, in addition to 5 novel common silent variants. We tested for association of the ABCA1 I/M823 variant with plasma HDL cholesterol in Canadian Inuit and found that M823/M823 homozygotes had significantly higher plasma HDL cholesterol compared with subjects with the other genotypes. The results provide proof of principle of the effectiveness of this approach to identify both rare and common ABCA1 genomic variants and also suggest that common amino acid variation in ABCA1 is a determinant of plasma HDL cholesterol in the general population.

ATP Binding Cassette Transporter 1↗
PubMed2000

Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree.

Among the Oji-Cree of northern Ontario, we previously identified a novel variant in the HNF1A gene, namely G319S, that was strongly associated with type 2 diabetes. However, the majority of subjects with diabetes did not have the HNF1A S319 variant, suggesting that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, we found that some of them had the PPARG A12 variant. After genotyping PPARG in the entire adult Oji-Cree population, we found that: 1) PPARG A12 was strongly associated with type 2 diabetes in women, but not men; 2) among women, the odds of being affected for carriers of PPARG A12 compared with noncarriers was 2.3 (95% confidence interval, 1.4-3.8); and 3) among women, affected carriers of PPARG A12 had a significantly earlier age-of-onset and/or age-at-diagnosis compared with noncarriers. When taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least two genes are involved in determining susceptibility to the disease in these people.

Adult↗