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Biomedical subjects

B D Mitchell

Publications and source records attributed to B D Mitchell.

At least 19 recordsLinked to original sources
PubMed2002

Novel neuropeptide Y1 and Y5 receptor gene variants: associations with serum triglyceride and high-density lipoprotein cholesterol levels.

Neuropeptide Y (NPY) appears to play a critical role in the integration of appetite and energy expenditure through NPY Y1 and Y5 receptor subtypes. Moreover, the NPY Y1 receptor is highly expressed on human adipocytes, where it inhibits lipolysis. The genes encoding these receptors are transcribed co-ordinately in opposite directions from a common promoter in a region of chromosome 4 that has been previously linked to triglyceride and small low-density lipoprotein (LDL) particle concentration. Therefore, the purpose of this investigation was to examine the relationship between polymorphisms in the genes encoding NPY Y1 and Y5 and the development of obesity and dyslipidemia. We screened the promoter and coding regions and identified four polymorphic variants. One of these, a cytosine to thymine (C-->T) substitution in the untranslated region between the genes for NPY Y1 and Y5 (allele frequency 0.11), was significantly associated with both lower fasting triglyceride level (152 vs 125 mg/dl), and higher high-density lipoprotein (HDL) concentrations (49 vs 45 mg/dl) (p < 0.01) in 306 obese subjects. Given the stimulatory effect of NPY on adipocyte lipoprotein lipase (LPL) activity, and the lack of association of other polymorphisms with serum lipid levels, we hypothesize that this is a gain-in-function polymorphism.

Adult↗
PubMed2001

Corticocortical and thalamocortical projections to layer I of the frontal neocortex in rats.

Layer I of the neocortex is a dense synaptic zone consisting of horizontal corticocortical and widespread layer VII projections, in addition to thalamic inputs. In order to determine the origin and extent of corticocortical and thalamocortical projections to layer I of the frontal/premotor area M2 of the rat neocortex, we have used fluorescent anatomical tracing methods to determine the precise sources of cortical and thalamic input to the rostral and caudal aspects of layer I of M2. Retrograde tracer diamidino yellow (DY), applied directly to the pial surface on rostral or caudal areas of rat M2 (RM2 and CM2, respectively) labeled cells ipsilaterally throughout layers II/III, V, and VII of the adjacent primary motor area and the parietal areas (SI and SII). In addition, retrograde transport labeled contralateral CM2 or RM2 in layers II/III and V at sites homotopic to either CM2 or RM2 application sites. Contralateral layer VII was retrogradely labeled by the application to layer I of CM2, but not by the RM2 application. Retrograde DY transport from layer I of RM2 or CM2 of was seen in the ventral medial (VM), ventral lateral (VL), and posterior (Po) thalamic nuclei. However layer I transport from CM2 additionally labeled the thalamic central medial (CM) nucleus, while the RM2 labeled the mediodorsal (MD) thalamic nucleus. Upon determination that thalamic nuclei VM and VL were of primary interest in this study, due to their dense retrograde labeling, injections of anterograde tracer rhodamine dextranamine (RDA) into VM or VL were performed in order to study the projection patterns of these nuclei to layer I of the frontal cortex. RDA injections into VM labeled fibers extending through layer I of both RM2 and CM2 and throughout the cingulate cortex. Injections of RDA into VL consistently labeled dense fibers in layer I of both CM2 and RM2, although labeling was sharply decreased anterior to CM2. This study adds to a growing body of evidence that projections to layer I from all sources of cortical input make a significant contribution to integration throughout the neocortex.

Amidines↗
PubMed2001

Aberrant apoptosis in the neurological mutant Flathead is associated with defective cytokinesis of neural progenitor cells.

Flathead is a rat neurological mutant which is phenotypically characterized by a flattened cranium, resting tremor, ataxia, progressive paralysis of the hind limbs, and death at 3-4 weeks after birth. Previous studies showed that rats homozygous for the mutation have a dramatically reduced brain size caused by a burst of apoptosis that begins after embryonic day 16 (E16) and which peaks at about E18. Late-developing structures such as the dentate gyrus, internal granule layer of the cerebellum, and superficial layers of the neocortex are severely depleted of cells. In the present study we have found that neurons and glia are both affected by the mutation. Immunohistochemical analysis with TAG-1, a marker for migratory neurons, revealed reduced staining in Fh neocortex and cerebellum, indicating that the mutation affects neuronal migration or a developmental event prior to it. Analysis of acutely dissociated neocortical cultures showed an accumulation of nestin-positive progenitor cells. Moreover, a substantial proportion of these progenitor cells were multinucleated with the nuclei organized as rosettes. Such multinucleated cells were also found in intact sections of the neocortex and the cerebellum where their presence was restricted to proliferative zones. Within the neocortex, the abundance of multinucleated progenitors is highest at E18 and decreases thereafter, thus correlating with the profile of cell death. This, along with the dramatically higher frequency of apoptosis among multinucleated cells, suggests that the aberrant cell death in Fh is due to defective cytokinesis that occurs in progenitor cells during late stages of brain development.

Animals↗
PubMed2001

Heritability of life span in the Old Order Amish.

Although a familial contribution to human longevity is recognized, the nature of this contribution is largely unknown. We have examined the familial contribution to life span in the Old Order Amish (OOA) population of Lancaster County, Pennsylvania. Analyses were conducted on 1,655 individuals, representing all those born prior to 1890 and appearing in the most widely available genealogy, surviving until at least age 30 years, and with known date of death. Mean age at death (+/-SD) in this population was 70.7 +/- 15.6 years, and this did not change appreciably over time. Parental and offspring ages at death were significantly correlated, as were ages of death among siblings. Offspring longevity was correlated with longevity of both parents, and in more or less additive fashion. For example, mean offspring age at death was 69.4 +/- 15.3 years in individuals for whom both parents died before the age of 75 years (n = 280) and increased to 73.5 +/- 16.0 years in individuals for whom neither parent died before the age of 75 years (n = 311). These differences were highly significant (P = 0.006). We estimated heritability of life span to be 25% +/- 5%, suggesting that the additive effects of genes account for one quarter of the total variability in life span in the OOA. We conclude that longevity is moderately heritable in the OOA, that the genetic effects are additive, and that genetic influences on longevity are likely to be expressed across a broad range of ages. Published 2001 Wiley-Liss, Inc.

Adult↗
PubMed2001

Using step-wise linear regression to detect "functional" sequence variants: application to simulated data.

Step-wise linear regression was used to detect the "functional" sequence variant in gene 6 responsible for phenotypic variation in traits Q1 and Q2. Prior to analysis, single-nucleotide polymorphisms (SNPs) that were in complete or near complete linkage disequilibrium were binned. In total, we identified 11 separate alleles (or allelic bins). Analyses were performed on all 50 replicates. The "functional" allele variant in gene 6 (at position 5782) accounted for 24% of the variation in Q1 and 11% of the variation in Q2. We detected a significant association between this SNP and Q1 in 90% of the replicates (i.e., in 45 of 50 replicates) and between this SNP and Q2 in 78% of the replicates. Although significant associations were also observed with some nonfunctional SNPs, our results nevertheless suggest that simple step-wise regression may play a useful role in analyzing sequence data. Some additional extensions to this approach are suggested.

Adult↗
PubMed2001

Replication of linkage to quantitative trait loci: variation in location and magnitude of the lod score.

Replication of linkage signals from independent samples is considered an important step toward verifying the significance of linkage signals in studies of complex traits. The purpose of this empirical investigation was to examine the variability in the precision of localizing a quantitative trait locus (QTL) by analyzing multiple replicates of a simulated data set with the use of variance components-based methods. Specifically, we evaluated across replicates the variation in both the magnitude and the location of the peak lod scores. We analyzed QTLs whose effects accounted for 10-37% of the phenotypic variance in the quantitative traits. Our analyses revealed that the precision of QTL localization was directly related to the magnitude of the QTL effect. For a QTL with effect accounting for > 20% of total phenotypic variation, > 90% of the linkage peaks fall within 10 cM from the true gene location. We found no evidence that, for a given magnitude of the lod score, the presence of interaction influenced the precision of QTL localization.

Chromosome Mapping↗
PubMed2001

Cadmium, copper, mercury, and zinc concentrations in tissues of the king crab (Pseudocarcinus gigas) from southeast Australian waters.

The concentrations of cadmium, copper, mercury, and zinc were determined in muscle (body, claw, and leg), hepatopancreas, and gill tissues of Pseudocarcinus gigas, an exceptionally large, long-lived, and deep-dwelling crab species. The accumulation patterns observed are discussed in terms of both intra- and interspecies variations, with particular attention to the possible consequences of the extreme size and depth range of P. gigas. Metal concentrations did not depend significantly on sex of the crab. Significant differences between tissues were detected for all metals, and the distribution of metal between the tissues was different for each metal. Significant correlations were found between metal concentrations in the various tissues and crab size, and these are discussed and rationalised. The concentrations of mercury and zinc in muscle tissue increased with crab size and were high compared to other crab species. The concentrations of cadmium and copper present in edible tissues were not especially high compared to other crab species, but the concentration of cadmium in the hepatopancreas is of dietary concern.

Animals↗
PubMed2001

Genetic contributions to plasma total antioxidant activity.

Oxidative stress plays important roles in a wide spectrum of pathological processes, such as atherosclerosis. Although several environmental factors are documented to influence redox metabolism, relatively little is known about genetic effects. In the present study, we evaluated genetic contributions to variation in plasma total antioxidant status (TAS), a measure of peroxyl-scavenging capacity, in 1337 members of 40 Mexican American families. TAS levels were significantly lower in women than in men (1.675+/-0.004 versus 1.805+/-0.005 mmol/L, respectively; P<0.001), and there was a significant decline of TAS levels with age in men but not in women (P<0.01 for the interaction). Quantitative genetic analysis indicated the heritability of TAS levels to be 0.509+/-0.052; ie, approximately 51% of the residual variance (after covariate adjustment) in TAS levels was due to the additive effects of genes (P<0.001). We have further observed a significant gene-by-smoking interaction (P<0.05). Additive genetic effects account for 83% of the residual phenotypic variance in TAS levels among smokers, but they account for only 49% in nonsmokers. However, genes contributing to TAS variation are the same in smokers and nonsmokers. Our study for the first time demonstrates that TAS, an indicator of redox homeostasis, is under strong genetic control, especially among smokers. With appropriate tools, such as genome screening, it should be possible to localize genes that regulate redox homeostasis and, ultimately, identify the DNA sequence variants predisposing subjects to oxidative damage.

Adolescent↗
PubMed2001

Genome-wide scan of obesity in the Old Order Amish.

To identify the genetic determinants of typical obesity, we performed a genome-wide scan of obesity-related traits using data from the Amish. Multipoint linkage analysis was performed using a variance components procedure on body mass index (BMI), waist circumference, percentage of body fat, and serum leptin concentrations. All 672 individuals were genotyped for 357 markers in 22 autosomes. We observed modest evidence for linkage, with the maximum log odds (lod) scores for linkage for these traits occurring on chromosomes 3p (percentage of body fat: lod = 1.61, near the peroxisome proliferator-activated receptor-alpha gene), 14q (waist: lod = 1.80), and 16p (leptin: lod = 1.72; BMI: lod = 1.68). We also tested for linkage to BMI-adjusted leptin concentrations and observed suggestive evidence for linkage on chromosome 10p (lod = 2.73), approximately 10-20 cM telomeric from obesity loci previously reported in French and German Caucasians. Two additional linkage signals for this trait were observed on chromosomes 7q (lod = 1.77, approximately 20 cM from the leptin gene) and 14q (lod = 2.47). Follow-up studies may be warranted to pursue some of these linkage signals, especially those detected near known obesity candidate genes, and those in regions coinciding with linkage signals reported previously.

Adipose Tissue↗
PubMed2001

Interactions between variants in the beta3-adrenergic receptor and peroxisome proliferator-activated receptor-gamma2 genes and obesity.

OBJECTIVE: Previous studies have reported modest associations between measures of obesity and the Trp64-Arg variant of the beta3-adrenergic receptor (ADRbeta3) and the Pro12Ala variant of the peronisome proliferator-activated receptor (PPAR)-gamma2. We hypothesized that these single gene variants may mark mutations that act through convergent pathways to produce synergistic effects on obesity. RESEARCH DESIGN AND METHODS: The sample included 453 subjects from 10 large Mexican-American families participating in the population-based San Antonio Family Heart Study. The effects of each gene variant singly and jointly were estimated as fixed effects using the measured genotype approach framework. Analyses were conditioned on the pedigree structures to account for the correlations among family members. Statistical significance was evaluated by the likelihood ratio test with adjustment for age, sex and diabetes status. RESULTS: The allele frequencies for the ADRbeta3 Trp64Arg and PPARgamma2 Pro12Ala variants were 18 and 12%, respectively. The ADRbeta3 variant was not significantly associated with any of the obesity-related traits, but subjects with the PPAR-gamma2 variant (n = 98) had significantly higher levels of lasting insulin (P = 0.03), leptin (P = 0.009), and waist circumference (P = 0.03) than those without. Subjects with the gene variants (n = 32) had significantly higher BMI, insulin, and leprtin levels than those with only the PPARgamma2 variant (n = 66) (P for interaction: 0.04, 0.02, and 0.01 for BMI, fasting insulin, and leptin, respectively). CONCLUSIONS: Our results suggest that epistatic models with genes that have modest individual effects may be useful in understanding the genetic underpinnings of typical obesity in humans.

Adipose Tissue↗
PubMed2000

Association among 5-year changes in weight, physical activity, and cardiovascular disease risk factors in Mexican Americans.

Recent changes in lifestyle have led to a global epidemic of obesity. To determine the associations of these changes with cardiovascular disease (CVD) risk, the authors correlated changes in CVD risk factors with changes in weight and physical activity in a population-based sample of 539 Mexican Americans in the San Antonio Heart Study in 1992-1999 who were examined twice approximately 5 years apart. Average weight change during that interval was 2.7 kg. While change in physical activity (expressed as percent change) was associated modestly only with change in low density lipoprotein cholesterol median diameter (p = 0.017), weight change was strongly and positively associated with unfavorable changes in lipid and lipoprotein traits, insulin levels, and blood pressure, explaining 2-10% of the variation in the risk factor changes during the interval. The unfavorable associations with weight gain tended to be more pronounced in lean compared with obese individuals and in men compared with women. However, the associations were significant for most CVD risk factors in all groups. In Mexican Americans, a population at high risk for obesity, weight change was positively correlated with metabolic variables associated with risk of CVD. Therefore, increasing adiposity in this population may tend to slow, or even reverse, the decline in CVD morbidity and mortality.

Adult↗
PubMed2000

QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31-34 in Old Order Amish.

BACKGROUND: Hypertension is a major risk factor for coronary heart disease, stroke, congestive heart failure, renal insufficiency, and peripheral vascular disease. Although the genetic contribution to variation in blood pressure is well recognized, the specific genes involved are mostly unknown. We carried out a genome-wide scan to identify loci influencing blood pressure in the Old Order Amish population of Lancaster County, Pennsylvania. METHODS AND RESULTS: Blood pressures were measured in 694 adult participants from families recruited without regard to blood pressure. We performed a quantitative linkage analysis by using 357 microsatellite markers. In multipoint analysis, strong evidence for linkage was observed with both diastolic (lod=3.36; P=0.00004) and to a lesser extent systolic (lod=1.64; P=0.003) blood pressure in the region of chromosome 2q31-34. Peak evidence for linkage occurred at map positions 217 and 221 cM from pter for diastolic and systolic blood pressure, respectively. CONCLUSIONS: A gene linked to familial primary pulmonary hypertension has recently been mapped to this same region, suggesting the intriguing hypothesis that other (attenuated) mutations in this same gene may influence variation in systolic and diastolic blood pressure in this population.

Adult↗
PubMed2000

Effects of the ApoE polymorphism on plasma lipoproteins in Mexican Americans.

PURPOSE: To evaluate the impact of apolipoprotein E (apoE) genotypes on lipoprotein measurements relative to that of other known cardiovascular risk factors in participants of a large population-based family study. METHODS: We measured concentrations of apoE, the major constituents of HDL (cholesterol, apoAI), LDL-C (cholesterol and apoB), and fraction of apoE in lipoprotein size classes in 859 participants of the San Antonio Family Heart Study, and then tested the association between the three common apoE genotypes (epsilon2epsilon3, epsilon3epsilon3, and epsilon3epsilon4) and lipoprotein traits using the measured genotype approach to account for residual familial correlations. RESULTS: Allele frequencies in this population for epsilon2, epsilon3, and epsilon4 were 3.5%, 89.6%, and 6.9%, respectively. As expected, adjusted apoE concentrations were highest in those with epsilon2epsilon3, intermediate in those with epsilon3epsilon3, and lowest in those with epsilon3epsilon4. The concentrations of total cholesterol, LDL-C and apoB were lowest in those with epsilon2epsilon3, intermediate in those with epsilon3epsilon3, and highest in those with epsilon3epsilon4. There was no significant effect of apoE genotypes on triglycerides, HDL-C, or apoAI levels. Compared to subjects with epsilon3epsilon4, subjects with epsilon2epsilon3 had relatively less apoE in LDL and HDL(1), and relatively more in HDL(2) and HDL(3) size fractions. The effect of apoE genotypes was significantly greater on apoB in women than in men. ApoE genotypes accounted for 4.5%, 12.3%, and 4.7% of the total genetic variation in apoB, apoE, and LDL-C, respectively. CONCLUSION: ApoE genotypes account for a modest, albeit significant, proportion of phenotypic variation in concentrations of LDL-C, apoB, and apoE, and distributions of apoE among lipoproteins in this population; these genotypes have a greater effect on apoB levels in women than in men.

Adolescent↗
PubMed2000

The Pro12Ala variant of peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with measures of obesity in Mexican Americans.

Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate adipocyte differentiation and gene expression. We tested the hypothesis that the Pro12Ala variant of PPAR-gamma2 is associated with obesity and type 2 diabetes-related traits in 921 subjects from the San Antonio Family Heart Study. Subjects with at least one Ala allele (n=210) had significantly higher body mass index (P=0.015) and waist circumference (P=0.028) and significantly higher levels of serum leptin (P= 0.022) than those without the allele. Further studies will determine whether the Pro12Ala variant itself, or other genetic variation at PPAR-gamma, is responsible for this association with measures of obesity in Mexican Americans.

Adult↗
PubMed2000

Genes influencing variation in serum osteocalcin concentrations are linked to markers on chromosomes 16q and 20q.

Osteocalcin (OC) is an important constituent of bone that is synthesized by osteoblasts. Serum levels of OC have been used as a biochemical marker of bone turnover. To identify the genes influencing variation in serum OC levels, we conducted a genome-wide scan in 429 individuals comprising 10 large multigenerational families. OC levels were measured by immunoassay, and genetic markers were typed at approximately 10-cM intervals across the genome. Quantitative trait linkage was tested using a multipoint analysis based on variance component methodology, adjusting for the effects of age, sex, and oral contraceptive use. Significance levels for linkage were obtained empirically, by Monte Carlo simulation. The heritability of OC levels in this population was 62 +/- 8%. We detected significant evidence for linkage between a quantitative trait locus influencing serum OC levels and markers on chromosome 16q, and suggestive evidence for linkage of OC levels with markers on chromosome 20q. The multipoint lod scores peaked at 3.35 on chromosome 16 and 2.78 on chromosome 20, corresponding to P values of 0.00004 and 0.00017, respectively. A potential candidate gene for bone formation in the linked region on chromosome 20 is CDMP1, which encodes cartilage-derived morphogenetic protein 1. Future studies should evaluate whether variation in CDMP1 or in other genes in the linked regions on chromosomes 16 and 20 influence the rate of bone turnover.

Adolescent↗
PubMed2000

Linkage of serum insulin concentrations to chromosome 3p in Mexican Americans.

Hyperinsulinemia predicts the development of type 2 diabetes, and family studies suggest that insulin levels are regulated in part by genes. We conducted a genome-wide scan to detect genes influencing variation in fasting serum insulin concentrations in 391 nondiabetic individuals from 10 large multigenerational families. Approximately 380 microsatellite markers with an average spacing of 10 cM were genotyped in all study subjects. Insulin concentrations measured by radioimmunoassay were transformed by their natural logarithms before analysis. In multipoint analysis, peak evidence for linkage occurred on chromosome 3p approximately 109 cM from pter in the region of 3p14.2-p14.1. The multipoint logarithm of odds (LOD) score was 3.07, occurring in the region flanked by markers D3S1600 and D3S1285 (P value by simulation <0.0001). In a two-point analysis, LOD scores ranged from 0.75 to 2.52 for the nine markers typed in the region spanning 88-143 cM from pter. The fasting insulin resistance index was highly correlated with fasting insulin concentrations in this sample and also provided strong evidence for linkage to this region (LOD = 2.99). There was no evidence in our genome-wide scan for linkage of insulin levels to any other chromosome. These results provide evidence that a gene-influencing variation in insulin concentrations exists on chromosome 3p. Possible candidate genes in this region include GBE1 and ACOX2, which encode enzymes involved in glycogen and fatty acid metabolism, respectively.

Adult↗
PubMed2000

Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.

OBJECTIVE: The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS: The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS: The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to <0.0001). CONCLUSIONS: Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.

Adult↗