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Biomedical subjects

William E Kraus

Publications and source records attributed to William E Kraus.

At least 19 recordsLinked to original sources
PubMed2025

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Humans↗
PubMed2007

Modest exercise prevents the progressive disease associated with physical inactivity.

Activity levels continue to decline as technology continues to engineer movement out of our environment. We summarize the findings from Studies Targeting Risk Reduction Interventions through Defined Exercise (STRRIDE) emphasizing the high cost of even short-term continued inactivity in sedentary, overweight, or mildly obese individuals. There seems to be a critical minimal level of physical activity required to maintain metabolic health. A modest amount of exercise seems to prevent metabolic deterioration.

Cardiovascular Diseases↗
PubMed2006

GATA2 is associated with familial early-onset coronary artery disease.

The transcription factor GATA2 plays an essential role in the establishment and maintenance of adult hematopoiesis. It is expressed in hematopoietic stem cells, as well as the cells that make up the aortic vasculature, namely aortic endothelial cells and smooth muscle cells. We have shown that GATA2 expression is predictive of location within the thoracic aorta; location is suggested to be a surrogate for disease susceptibility. The GATA2 gene maps beneath the Chromosome 3q linkage peak from our family-based sample set (GENECARD) study of early-onset coronary artery disease. Given these observations, we investigated the relationship of several known and novel polymorphisms within GATA2 to coronary artery disease. We identified five single nucleotide polymorphisms that were significantly associated with early-onset coronary artery disease in GENECARD. These results were validated by identifying significant association of two of these single nucleotide polymorphisms in an independent case-control sample set that was phenotypically similar to the GENECARD families. These observations identify GATA2 as a novel susceptibility gene for coronary artery disease and suggest that the study of this transcription factor and its downstream targets may uncover a regulatory network important for coronary artery disease inheritance.

Adult↗
PubMed2006

Total nitrogen oxide following exercise testing reflects endothelial function and discriminates health status.

Nitric oxide (NO) bioavailability is important in vascular health, but unsuitable as a clinical measure due to biological oxidation. Total nitrogen oxides (NO(x)) are stable but background nitrate levels make it difficult to detect disease-based variation. We investigated the clinical discriminatory value of NO(x) as it relates to exercise capability (VO(2peak)) and brachial artery reactivity (BAR, an NO-dependent measure of endothelial health), in healthy (H), increased risk (RF), and known cardiovascular disease (CVD) subjects. BAR was measured using forearm occlusion/hyperemia stimulus. Subjects performed a maximal graded exercise test (GXT). Blood at rest, exercise termination, and 10 min into recovery was mixed equally with 0.1 M NaOH at 4 degrees C, filtered, and stored at -70 degrees C. NO(x) was measured by chemiluminescence. Seven of the RF group then exercise-trained for 6 months prior to retesting. The H group (n = 12) was younger, had higher VO(2peak), HDL levels, and baseline NO(x) values than the RF (n = 15) and CVD (n = 10) groups. NO(x) increased from baseline to recovery in the H group only (75.85 +/- 19.04 microM vs 97.76 +/- 31.93 microM; P <or= 0.01). BAR was greater in the H versus CVD group (7.24 +/- 3.78% vs 2.59 +/- 3.53%; P <or= 0.01). The relation between VO(2peak) and NO(x) recovery was significant across groups (r = 0.71, P <or= 0.01). Following training the RF subjects (n = 7) increased VO(2peak) (29.98 +/- 6.74 to 33.08 +/- 5.57 ml kg(-1) min(-1); P <or= 0.05), BAR (3.19 +/- 3.96 to 6.86 +/- 4.81%; P <or= 0.05), and recovery NO(x) (18.29 +/- 6.46 to 66.48 + 21.11 microM; P <or= 0.01). These findings suggest that plasma NO(x) following GXT discriminate cardiovascular disease status, are related to regional endothelial function, and respond favorably to exercise training.

Adult↗
PubMed2006

Obesity and physical activity: a review.

BACKGROUND AND METHODS: Obesity has become a problem of epidemic proportions in the U.S., with nearly two thirds of American adults being either overweight or obese. Current data suggest that this trend remains on the rise and threatens many of the gains that have been made in the prevention and treatment of heart disease. Exercise has long been considered an integral component of weight management, but available evidence suggests that exercise alone is a relatively inefficient means for losing weight. In contrast, regular exercise appears crucial in the prevention of weight gain and successful maintenance of weight loss, and in the fostering of cardiovascular health. This article reviews the available literature regarding the role of exercise in the prevention and treatment of obesity and evaluates the adequacy of current national guidelines.

Body Composition↗
PubMed2006

Response of high-sensitivity C-reactive protein to exercise training in an at-risk population.

BACKGROUND: High-sensitivity C-reactive protein (hsCRP) is promoted as an independent predictor of atherosclerotic risk. In addition, cardiorespiratory fitness is inversely related to hsCRP in single-sex cross-sectional analyses. Our objective was to determine if modulating fitness with exercise training imposes changes in high-sensitivity C-reactive protein in a mixed-sex population at risk for cardiovascular disease. METHODS: We studied baseline and postintervention plasma hsCRP in 193 sedentary, overweight to mildly obese, dyslipidemic men and women who were randomized to 6 months of inactivity or 1 of 3 aerobic exercise groups: low amount-moderate intensity (energy equivalent of approximately 19.3 km/wk at 40%-55% peak VO2), low amount-high intensity (energy equivalent of approximately 19.3 km/wk at 65%-80% peak VO2), or high amount-high intensity (energy equivalent of approximately 32.2 km/wk at 65%-80% peak VO2). RESULTS: At baseline, the study population was at intermediate to high cardiovascular risk as defined by hsCRP. Cardiorespiratory fitness was inversely related to hsCRP (P < .001) even after adjusting for significant and expected sex differences. Fitness, hormone replacement therapy use, and high-density lipoprotein cholesterol accounted for the sex difference in baseline hsCRP. Fitness, high-density lipoprotein cholesterol, fasting insulin, hormone replacement therapy, and visceral adiposity were all independent predictors for baseline hsCRP (r2 = 0.34 for the entire model, P < .0001). However, despite significant improvements in fitness, visceral adiposity, subcutaneous adiposity, and insulin sensitivity, hsCRP did not change in response to exercise training (P > .20). CONCLUSIONS: Cardiorespiratory fitness is inversely related to hsCRP independent of sex and accounts for most of the large sex disparity in hsCRP. Nonetheless, in the absence of a significant change in diet, 6 months of aerobic exercise training does not produce a significant change in hsCRP in an at-risk population.

Adult↗
PubMed2005

Inactivity, exercise, and visceral fat. STRRIDE: a randomized, controlled study of exercise intensity and amount.

Despite the importance of randomized, dose-response studies for proper evaluation of effective clinical interventions, there have been no dose-response studies on the effects of exercise amount on abdominal obesity, a major risk factor for metabolic syndrome, diabetes, and cardiovascular disease. One hundred seventy-five sedentary, overweight men and women with mild to moderate dyslipidemia were randomly assigned to participate for 6 mo in a control group or for approximately 8 mo in one of three exercise groups: 1) low amount, moderate intensity, equivalent to walking 12 miles/wk (19.2 km) at 40-55% of peak oxygen consumption; 2) low amount, vigorous intensity, equivalent to jogging 12 miles/wk at 65-80% of peak oxygen consumption; or 3) high amount, vigorous intensity, equivalent to jogging 20 miles/wk (32.0 km). Computed tomography scans were analyzed for abdominal fat. Controls gained visceral fat (8.6 +/- 17.2%; P = 0.001). The equivalent of 11 miles of exercise per week, at either intensity, prevented significant accumulation of visceral fat. The highest amount of exercise resulted in decreased visceral (-6.9 +/- 20.8%; P = 0.038) and subcutaneous (-7.0 +/- 10.8%; P < 0.001) abdominal fat. Significant gains in visceral fat over only 6 mo emphasize the high cost of continued inactivity. A modest exercise program, consistent with recommendations from the Centers for Disease Control/American College of Sports Medicine (CDC/ACSM), prevented significant increases in visceral fat. Importantly, a modest increase over the CDC/ACSM exercise recommendations resulted in significant decreases in visceral, subcutaneous, and total abdominal fat without changes in caloric intake.

Abdominal Fat↗
PubMed2005

Effects of exercise training amount and intensity on peak oxygen consumption in middle-age men and women at risk for cardiovascular disease.

STUDY OBJECTIVES: Although increasing aerobic fitness by exercise training is advocated as part of a healthy lifestyle, studies examining the different effects of intensity and amount on peak consumption (V(O2)) remain sparse. DESIGN: This randomized controlled trial compared the effects of three different exercise regimens differing in amount and intensity on fitness improvements. PARTICIPANTS: Overweight men and women with mild-to-moderate dyslipidemia were recruited. INTERVENTIONS: The exercise groups were as follows: (1) low amount/ moderate intensity (LAMI, n = 25), the caloric equivalent of walking 19 kilometers (km)/wk at 40 to 55% of peak V(O2); (2) low amount/high intensity (LAHI, n = 36), the equivalent of jogging 19 km/wk at 65 to 80% of peak V(O2); (3) high amount/high intensity (HAHI, n = 35), the equivalent of jogging 32 km/wk at 65 to 80% of peak V(O2); and (4) a control group (n = 37). MEASUREMENTS AND RESULTS: Peak V(O2) and time to exhaustion (TTE) were tested before and after 7 to 9 months of training. All exercise groups increased peak V(O2) and TTE compared to baseline (p < or = 0.001). Improvements in peak V(O2) were greater in the LAHI and HAHI groups compared to the control group (p < 0.02); HAHI group improvements were greater than the LAMI group (p < 0.02) and the LAHI group (p < 0.02). Increased TTE for all exercise groups was higher compared to the control group (p < 0.001) CONCLUSIONS: Exercising at a level of 19 km/wk at 40 to 55% of peak V(O2) is sufficient to increase aerobic fitness levels, and increasing either exercise intensity or the amount beyond these parameters will yield additional separate and combined effects on markers of aerobic fitness. Therefore, it is appropriate to recommend mild exercise to improve fitness and reduce cardiovascular risk yet encourage higher intensities and amounts for additional benefit.

Adult↗
PubMed2004

Exercise training increases electron and substrate shuttling proteins in muscle of overweight men and women with the metabolic syndrome.

Aerobic conditioned muscle shows increased oxidative metabolism or glucose relative to untrained muscle at a given absolute exercise intensity. The studies of a targeted risk reduction intervention through defined exercise (STRRIDE) study is an aerobic exercise intervention in men and women with features of metabolic syndrome (Kraus WE, Torgan CE, Duscha BD, Norris J, Brown SA, Cobb FR, Bales CW, Annex BH, Samsa GP, Houmard JA, and Slentz CA, Med Sci Sports Exerc 33: 1774-1784, 2001), with four muscle biopsies taken during training and detraining time points. Here, we expanded a previous study (Hittel DS, Kraus WE, and Hoffman EP, J Physiol 548: 401-410, 2003) and used mRNA profiling to investigate gene transcripts associated with energy and substrate metabolism in STRRIDE participants. We found coordinate regulation of key metabolic enzymes with aerobic training in metabolic syndrome (aspartate aminotransferase 1, lactate dehydrogenase B, and pyruvate dehydrogenase-alpha(1)). All were also quickly downregulated by detraining, although the induction was not an acute response to activity. Protein and enzymatic assays were used to validate mRNA induction with aerobic training and loss with detraining (96 h to 2 wk) in 10 male and 10 female STRRIDE subjects. We propose that training coordinately increases the levels of aspartate aminotransferase 1, lactate dehydrogenase B, and pyruvate dehydrogenase-alpha(1) subunit, increasing glucose metabolism in muscle by liberating pyruvate for oxidative metabolism and, therefore, limiting lactate efflux. Serial measurement of fasting plasma lactate from 62 subjects from the same exercise group demonstrated a significant decrease of circulating lactate with training. We also found evidence for sex-specific molecular remodeling of muscle with ubiquinol-cytochrome c reductase core protein II, a component of mitochondrial respiratory complex III, which showed an increase after training that was specific to women. These biochemical adaptations complement existing molecular models for improved glucose tolerance with exercise intervention in prediabetic individuals.

Adult↗
PubMed2004

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.

Adult↗
PubMed2004

Stretch-induced nitric oxide modulates mechanical properties of skeletal muscle cells.

In this study, we examined the hypothesis that stretch-induced (nitric oxide) NO modulates the mechanical properties of skeletal muscles by increasing accumulation of protein levels of talin and vinculin and by inhibiting calpain-induced proteolysis, thereby stabilizing the focal contacts and the cytoskeleton. Differentiating C(2)C(12) myotubes were subjected to a single 10% step stretch for 0-4 days. The apparent elastic modulus of the cells, E(app), was subsequently determined by atomic force microscopy. Static stretch led to significant increases (P < 0.01) in E(app) beginning at 2 days. These increases were correlated with increases in NO activity and neuronal NO synthase (nNOS) protein expression. Expression of talin was upregulated throughout, whereas expression of vinculin was significantly increased only on days 3 and 4. Addition of the NO donor l-arginine onto stretched cells further enhanced E(app), NOS activity, and nNOS expression, whereas the presence of the NO inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME) reversed the effects of mechanical stimulation and of l-arginine. Overall, viscous dissipation, as determined by the value of hysteresis, was not significantly altered. For assessment of the role of vinculin and talin stability, cells treated with l-NAME showed a significant decrease in E(app), whereas addition of a calpain inhibitor abolished the effect. Thus our results show that NO inhibition of calpain-initiated cleavage of cytoskeleton proteins was correlated with the changes in E(app). Together, our data suggest that NO modulates the mechanical behavior of skeletal muscle cells through the combined action of increased talin and vinculin levels and a decrease in calpain-mediated talin proteolysis.

Animals↗
PubMed2004

Effects of the amount of exercise on body weight, body composition, and measures of central obesity: STRRIDE--a randomized controlled study.

BACKGROUND: Obesity is a major health problem due, in part, to physical inactivity. The amount of activity needed to prevent weight gain is unknown. OBJECTIVE: To determine the effects of different amounts and intensities of exercise training. DESIGN: Randomized controlled trial (February 1999-July 2002). SETTING AND PARTICIPANTS: Sedentary, overweight men and women (aged 40-65 years) with mild to moderate dyslipidemia were recruited from Durham, NC, and surrounding communities. INTERVENTIONS: Eight-month exercise program with 3 groups: (1) high amount/vigorous intensity (calorically equivalent to approximately 20 miles [32.0 km] of jogging per week at 65%-80% peak oxygen consumption); (2) low amount/vigorous intensity (equivalent to approximately 12 miles [19.2 km] of jogging per week at 65%-80%), and (3) low amount/moderate intensity (equivalent to approximately 12 miles [19.2 km] of walking per week at 40%-55%). Subjects were counseled not to change their diet and were encouraged to maintain body weight. MAIN OUTCOME MEASURES: Body weight, body composition (via skinfolds), and waist circumference. RESULTS: Of 302 subjects screened, 182 met criteria and were randomized and 120 completed the study. There was a significant (P<.05) dose-response relationship between amount of exercise and amount of weight loss and fat mass loss. The high-amount/vigorous-intensity group lost significantly more body mass (in mean [SD] kilograms) and fat mass (in mean [SD] kilograms) (-2.9 [2.8] and -4.8 [3.0], respectively) than the low-amount/moderate-intensity group (-0.9 [1.8] and -2.0 [2.6], respectively), the low-amount/vigorous-intensity group (-0.6 [2.0] and -2.5 [3.4], respectively), and the controls (+1.0 [2.1] and +0.4 [3.0], respectively). Both low-amount groups had significantly greater improvements than controls but were not different from each other. Compared with controls, all exercise groups significantly decreased abdominal, minimal waist, and hip circumference measurements. There were no significant changes in dietary intake for any group. CONCLUSIONS: In nondieting, overweight subjects, the controls gained weight, both low-amount exercise groups lost weight and fat, and the high-amount group lost more of each in a dose-response manner. These findings strongly suggest that, absent changes in diet, a higher amount of activity is necessary for weight maintenance and that the positive caloric imbalance observed in the overweight controls is small and can be reversed by a modest amount of exercise. Most individuals can accomplish this by walking 30 minutes every day.

Adult↗
PubMed2004

Gender and racial differences in lipoprotein subclass distributions: the STRRIDE study.

Recent research has focused on the potential atherogenicity of various lipoprotein subclasses and their link to coronary heart disease (CHD) risk. This investigation seeks to identify differences in lipoprotein subclass distributions among a biracial, middle-aged population, while controlling for a number of confounding risk factors. Fasting plasma samples were analyzed in 285 sedentary, mildly dyslipidemic, overweight individuals between 40 and 65 years with no known history of CHD or diabetes. Women had lower levels of small and medium LDL, medium VLDL, large VLDL, and small HDL with a much higher concentration of large HDL than men. Whites had significantly more IDL, small LDL, medium VLDL, and large VLDL with lower levels of large LDL than blacks. HDL and LDL size were larger among blacks and women; VLDL size was greater among whites and men. There was also a trend for men to have more LDL particles than women and whites to have a higher LDL particle concentration than blacks. Within this homogenous population, there were distinct differences between gender and racial groups. Blacks and women had less atherogenic profiles than whites and men, which was not evident from the standard lipid panel.

Adult↗
PubMed2004

Agreement between a brief mailed screener and an in-depth telephone survey: observations from the Fresh Start study.

Brief screening instruments can roughly characterize individual behavior and target those most in need of change. However, the level of agreement between abbreviated and full-scale instruments is often unknown. We determined agreement between a brief screener and an in-depth survey for assessing eligibility into a randomized controlled trial to improve lifestyle behaviors among cancer survivors who consumed diets with >or=30% total energy from fat or fewer than five servings of fruits and vegetables per day, and/or who exercised <150 min/wk. Responses of 203 subjects to mailed screeners, which included scales from the National Cancer Institute (NCI)Percent Energy from Fat Screener and 5-A-Day trials, and one item on exercise, were compared with data from telephone interviews using the Diet History Questionnaire and the 7-Day Physical Activity Recall. Moderate correlations and fair agreement existed between screener and survey for intakes of fat [ r =0.54 ( P <.0001)/kappa statistic (ks)=0.35] and fruits and vegetables [ r =0.50 ( P <.0001)/ks=0.32], whereas agreement was low for exercise (ks=0.15). NCI and 5-A-Day screening instruments perform relatively well in targeting cancer survivors most in need of dietary change. Decisions to use brief screening instruments should be based on available resources and tolerance for misclassification.

Adult↗
PubMed2004

The effect of the PREMIER interventions on insulin sensitivity.

OBJECTIVE: This ancillary study of PREMIER sought to determine the effects on insulin sensitivity of a comprehensive behavioral intervention for hypertension with and without the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. RESEARCH DESIGN AND METHODS: Participants were assigned to one of three nonpharmacologic interventions for blood pressure (group A, advice only; group B, established; and group C, established plus DASH). The established intervention included weight loss, reduced sodium intake, increased physical activity, and moderate alcohol intake; the DASH dietary pattern was added to the established intervention for those in group C. The DASH dietary pattern is high in fruits, vegetables, and low-fat dairy products while being lower in total fat, saturated fat, and cholesterol. It is abundant in nutrients such as magnesium, calcium, and protein, which have been associated with improved insulin sensitivity. Insulin sensitivity was measured at baseline and at 6 months using the frequently sampled intravenous glucose tolerance test with minimal model analysis. RESULTS: Both intervention groups decreased total calories, percentage of calories from fat, and sodium intake to similar levels, with similar amounts of energy expenditure and weight loss. Covariate differences seen only in group C included increased intake of protein, potassium, calcium, and magnesium. Compared with control subjects, insulin sensitivity improved significantly only in group C, from 1.96 to 2.95 (P = 0.047). Group B did have a significant decrease in fasting insulin and glucose, but the changes in insulin sensitivity did not reach statistical significance when compared with control subjects. CONCLUSIONS: These results suggest that including the DASH dietary pattern as part of a comprehensive intervention for blood pressure control enhances insulin action beyond the effects of a comprehensive intervention that does not include DASH.

Adult↗