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S B Harris

Publications and source records attributed to S B Harris.

At least 37 records · Page 2Linked to original sources
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

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

Vitrification enhancement by synthetic ice blocking agents.

Small concentrations of the synthetic polymer polyvinyl alcohol (PVA) were found to inhibit formation of ice in water/cryoprotectant solutions. Ice inhibition improved with decreasing molecular weight. A PVA copolymer of molecular weight 2 kDa consisting of 20% vinyl acetate was found to be particularly effective. PVA copolymer concentrations of 0.001, 0.01, 0.1, and 1% w/w decreased the concentration of glycerol required to vitrify in a 10-ml volume by 1, 3, 4, and 5% w/w, respectively. Dimethyl sulfoxide concentrations required for vitrification were also reduced by 1, 2, 2, and 3% w/w, respectively. Crystallization of ice on borosilicate glass in contact with cryoprotectant solutions was inhibited by only 1 ppm of PVA copolymer. Devitrification of ethylene glycol solutions was also strongly inhibited by PVA copolymer. Visual observation and differential scanning calorimeter data suggest that PVA blocks ice primarily by inhibition of heterogeneous nucleation. PVA thus appears to preferentially bind and inactivate heterogeneous nucleators and/or nascent ice crystals in a manner similar to that of natural antifreeze proteins found in cold-hardy fish and insects. Synthetic PVA-derived ice blocking agents can be produced much less expensively than antifreeze proteins, offering new opportunities for improving cryopreservation by vitrification.

Calorimetry, Differential Scanning↗
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

A comparison of dynamic extension splinting and controlled active mobilization of complete divisions of extensor tendons in zones 5 and 6.

We present a prospective randomized trial of two groups of 50 patients each having complete zone 5 and 6 extensor tendon injuries. These were rehabilitated by the use of either a dynamic outrigger splint or a palmar blocking splint. The results were analysed using the Miller and TAM assessments. Good and excellent results were achieved in 95 and 98% of cases following dynamic outrigger mobilization and 93 and 95% of cases using palmar blocking splint mobilization, using the Miller and TAM assessments respectively. There was no statistical difference in the results obtained between the two groups. Therefore, we prefer the latter technique which is simple, cheap, more convenient and requires less therapy time.

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

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↗
PubMed2000

Association between PON1 L/M55 polymorphism and plasma lipoproteins in two Canadian aboriginal populations.

Serum paraoxonase circulates on a subfraction of high density lipoproteins and appears to use phospholipids on both low and high density lipoprotein particles as a physiological substrate. This functional relationship could explain the reported associations between common variation in the PON1 gene--at codons 55 and 192--and phenotypes related to atherosclerosis and lipoprotein metabolism. We evaluated associations between plasma lipoproteins and PON1 L/M55, PON1 Q/R192 and PON2 A/G148 polymorphisms in samples from two Canadian aboriginal populations, namely the Oji-Cree and the Inuit. In diabetic Oji-Cree, we found that carriers of PON1 M55 had a higher mean plasma triglyceride concentration than non-carriers. In non-diabetic Oji-Cree, we found that carriers of PON1 M55 had higher mean plasma concentrations of total and low density lipoporetein cholesterol and apo B than non-carriers. In Inuit, we found that carriers of PON1 M55 had higher mean plasma concentrations of total and low density lipoprotein cholesterol than non-carriers. The other polymorphic markers were not associated with variation in any plasma lipoprotein trait. Thus, the PON1 M55 allele appeared to be associated with deleterious changes in the plasma lipoprotein profile from two independent Canadian aboriginal samples. These results suggest that common variation in PON1 codon 55 is associated with variation of intermediate traits in plasma lipoprotein metabolism in aboriginal Canadians.

Adolescent↗
PubMed2000

Clinical utility of HNF1A genotyping for diabetes in aboriginal Canadians.

OBJECTIVE: To determine the diagnostic performance characteristics of HNF1A genotyping for diabetes and impaired glucose tolerance (IGT) in Canadian Oji-Cree Indians. RESEARCH DESIGN AND METHODS: We studied all Oji-Cree subjects > or = 50 years of age (96 subjects) who had participated in a community-wide prevalence survey for type 2 diabetes. Subjects were classified either as having "disease," which included type 2 diabetes and IGT, or not. All subjects were genotyped for the HNF1A G319S mutation. RESULTS: The prevalence of disease in this group was 65.7%, of whom 71.4% had type 2 diabetes. For a carrier of HNF1A S319, the specificity, sensitivity, and positive and negative predictive values were 97.0, 30.1, 95.0, and 42.1%, respectively. When the pretest disease prevalence was accounted for, the probability of disease after a positive test was 97.2%, and the probability of disease after a negative test was 42.2%. The values were very similar for the subgroup of subjects with type 2 diabetes alone. CONCLUSIONS: The HNF1A genotype appears to be the most specific genetic test yet reported for the prediction of a common multifactorial disease by applying present-day standards of clinical epidemiology in molecular genetics. A positive test result had particular diagnostic value in the Oji-Cree: a subject with HNF1A S319 was virtually certain of having diabetes or IGT by 50 years of age. In contrast, a subject without HNF1A S319 had a reduced risk compared with the age-specific prevalence but was not totally risk-free. Because HNF1A S319 was not the only predisposing factor for diabetes in the Oji-Cree, subjects without HNF1A S319 were still at some risk for diabetes or IGT.

Canada↗
PubMed1999

Genome-wide scanning for type 2 diabetes susceptibility in Canadian Oji-Cree, using 190 microsatellite markers.

We undertook a genome-wide scan using 190 markers with an average separation of 20 cM in 49 Canadian Oji-Cree sib pairs affected with type 2 diabetes. Four of these markers, one each on chromosomes 6, 8, 16, and 22, showed both suggestive linkage and suggestive association with type 2 diabetes in the Oji-Cree. None of these markers corresponded to any chromosomal region or marker that has so far been linked with type 2 diabetes in other populations. Thus, there might be several genetic loci that confer susceptibility to type 2 diabetes in this study sample. We are following up on these preliminary leads by increasing the density of the markers within these linked and associated regions, and also by increasing the number of study subjects. Also, we found instances in which there were wide disparities between the Oji-Cree and reference Caucasians with respect to marker heterozygosity. This suggests that a particular set of markers for genome-wide scanning will have different informativeness in different ethnic groups. Thus, different marker sets will likely be required for different ethnic groups in order to maximize their information content for linkage calculations.

Adult↗
PubMed1999

The ADD1 G460W polymorphism is not associated with variation in blood pressure in Canadian Oji-Cree.

Since adducin modulates cellular sodium retention, its follows that ADD1, which encodes the alpha-subunit of adducin, is an attractive candidate gene for blood pressure variation. Association studies examining the relationship between polymorphism at ADD1 codon 460 (G460W) and both hypertension and blood pressure, which were performed in a variety of human population samples derived from different genetic backgrounds, have given inconsistent results. We examined the association between the ADD1 G460W polymorphism and variation in blood pressure in a sample of non-diabetic, largely normotensive Canadian Oji-Cree from an isolated community in Northern Ontario. Among 481 Oji-Cree subjects, we measured blood pressure and related clinical phenotypes and determined genotypes of ADD1 G460W. We observed an allele frequency of 0.08 for the ADD1 W460 variant, which is among the lowest so far observed in human populations. We found significant associations between variation in both systolic and diastolic blood pressure and gender, age, body mass index (BMI), and treatment for hypertension. However, we found no association between the ADD1 W460 allele and increased blood pressure, nor did we observe a higher frequency of the W460 allele in a hypertensive subgroup compared with normotensive subjects. While the low sample frequency of ADD1 W460 is consistent with the low sample prevalence of hypertension, the absence of a specific association with both blood pressure and hypertension suggests that the ADD1 W460 variant is not an important determinant of blood pressure among individuals of this genetic background.

Adolescent↗
PubMed1999

Increased plasma apolipoprotein B-containing lipoproteins associated with increased urinary albumin within the microalbuminuria range in type 2 diabetes.

BACKGROUND: While increased plasma concentrations of apolipoprotein B-containing lipoproteins are a feature of diabetic nephropathy associated with nephrotic range proteinuria, the relationship of plasma lipoproteins to increasing urine albumin concentration within the microalbuminuria range is less well-studied. METHODS: We, therefore, examined the relationship between urine albumin excretion in the 0 to 100 mg/L range and plasma lipoproteins in 56 Oji-Cree with type 2 diabetes. RESULTS: We found a significant direct relationship between the urinary albumin concentration within this low range and the plasma concentrations of total and low density lipoprotein cholesterol and apolipoprotein B (p = 0.015, 0.0032, and 0.0019, respectively). CONCLUSIONS: These results suggest that the well-known relationship between gross proteinuria and hyperlipidemia may extend into the microalbuminuric range in subjects with type 2 diabetes.

Adult↗