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ABSTRACT: OBJECTIVE: To test whether equivalent energy expenditure by moderate-intensity (eg, walking) and vigorous-intensity exercise (eg, running) provides equivalent health benefits.Approach and Results-We used the National Runners' (n=33 060) and Walkers' (n=15 945) Health Study cohorts to examine the effect of differences in exercise mode and thereby exercise intensity on coronary heart disease (CHD) risk factors. Baseline expenditure (metabolic equivant hours per day [METh/d]) was compared with self-reported, physician-diagnosed incident hypertension, hypercholesterolemia, diabetes mellitus, and CHD during 6.2 years follow-up. Running significantly decreased the risks for incident hypertension by 4.2% (P<10(-7)), hypercholesterolemia by 4.3% (P<10(-14)), diabetes mellitus by 12.1% (P<10(-5)), and CHD by 4.5% per METh/d (P=0.05). The corresponding reductions for walking were 7.2% (P<10(-7)), 7.0% (P<10(-8)), 12.3% (P<10(-4)), and 9.3% (P=0.01). Relative to <1.8 METh/d, the risk reductions for 1.8 to 3.6, 3.6 to 5.4, 5.4 to 7.2, and ≥7.2 METh/d were as follows: (1) 10.0%, 17.7%, 25.1%, and 34.9% from running and 14.0%, 23.8%, 21.8%, and 38.3% from walking for hypercholesterolemia; (2) 19.7%, 19.4%, 26.8%, and 39.8% from running and 14.7%, 19.1%, 23.6%, and 13.3% from walking for hypertension; and (3) 43.5%, 44.1%, 47.7%, and 68.2% from running, and 34.1%, 44.2% and 23.6% from walking for diabetes mellitus (walking >5.4 METh/d excluded for too few cases). The risk reductions were not significantly different for running than walking for diabetes mellitus (P=0.94), hypercholesterolemia (P=0.06), or CHD (P=0.26), and only marginally greater for walking than running for hypercholesterolemia (P=0.04). CONCLUSIONS: Equivalent energy expenditures by moderate (walking) and vigorous (running) exercise produced similar risk reductions for hypertension, hypercholesterolemia, diabetes mellitus, and possibly CHD.
Arteriosclerosis Thrombosis and Vascular Biology 04/2013; · 6.37 Impact Factor
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ABSTRACT: Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses.
Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments.
The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2-24.6 nm) and LDL-IVa (23.3-24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values.
Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol.
ClinicalTrials.gov NCT00000553.
PLoS ONE 01/2013; 8(2):e56782. · 4.09 Impact Factor
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ABSTRACT: To assess the clinical utility of measuring high-density lipoprotein (HDL) subfractions to assess coronary heart disease (CHD) risk.
Literature review of 80 published investigations.
Measurements of HDL2b by gradient gel electrophoresis provided more consistent evidence of CHD risk than measurement of HDL2 cholesterol. Five of the seven studies that compared the extent or progression of atherosclerosis with gradient gel electrophoresis estimates of HDL subclasses (71%) assigned statistical significance to HDL2b. Ten of the 11 case-control comparisons (91%) reported lower HDL2b in cases. In contrast, of the 16 association studies relating HDL2 cholesterol and HDL3 cholesterol to extent of disease, five reported no significant relationships with either subfraction, two reported significant relationships with both HDL2 and HDL3 cholesterol, four reported significant relationships with HDL2 but not HDL3 cholesterol, and five reported relationships with HDL3 but not HDL2 cholesterol. Forty-five percent of the case-control comparisons reported that both HDL2 cholesterol and HDL3 cholesterol were significantly lower in cases than controls, 17% failed to find significance for either subfraction, and the remainder reported significantly lower values in cases for HDL2 cholesterol only (26%) or HDL3 cholesterol only (11%). On average, the case-control differences were similar for HDL2 (-0.12 ± 0.01 mmol/L) and HDL3 cholesterol (-0.10 ± 0.02 mmol/L), although relative to controls, the percent reduction was twice as great for HDL2 (-25.7 ± 2.9%) than HDL3 cholesterol (-12.1 ± 1.5%). Eight prospective studies were identified and four reported that both HDL2 and HDL3 predicted lower risk for CHD, one reported reductions in risk for HDL2 but not HDL3 cholesterol, and three reported reductions in risk for HDL3 but not HDL2 cholesterol. None of the prospective studies show that measurements of HDL cholesterol subfractions improve the identification of persons at risk.
HDL2 and HDL3 cholesterol do not distinguish cardioprotective differences between HDL subclasses. More extensive characterization of HDL particles by one or two dimensional gel electrophoresis, ion mobility, or ultracentrifugation may provide more specific information about CHD risk than the measurement of HDL cholesterol, HDL3 cholesterol, or HDL2 cholesterol.
Journal of Clinical Lipidology 11/2012; 6(6):496-523. · 1.58 Impact Factor
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Circulation 11/2011; 124(21):2283-4. · 14.74 Impact Factor
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Paul T Williams
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ABSTRACT: Vigorous physical activity (running) has been shown to attenuate the association between diet and body weight. Walking is the most popular physical activity, but is a moderate-intensity physical activity because it requires less than sixfold the energy expenditure of sitting at rest. We therefore examined whether reported distance walked per week affected the relationship of diet to BMI and circumferences of the waist, hip, and chest in 30,014 female and 7,133 male participants of the National Walkers' Health Study. Reported meat and fruit intakes served as indicators of high-risk diets for weight gain. The analyses showed that higher meat and lower fruit intake were significantly and consistently associated with greater BMI and waist circumference at all activity levels. Longer usual walking distance significantly attenuated the concordant relationships of diet with women's BMIs (P < 10(-8)), men's BMIs (P = 0.04), and women's waist (P < 10(-6)), hip (P = 0.0001), and chest circumferences (P < 10(-5)). Compared to walkers who averaged <1.5 km/day, the association of diet with adiposity in subjects who walked ≥1.5 km/day was reduced 21% in women and 31% in men for BMI; 20% in women and 27% in men for waist circumference; 19% for women's hip circumference; and 26% for women's chest circumference. Thus we conclude that diets characterized by high-meat/low-fruit intake were significantly associated with greater BMI, and this association was attenuated by moderate physical activity. The weaker results in men than women probably related to the smaller sample size, and reduced statistical power of the men.
Obesity 10/2011; 20(9):1929-35. · 4.28 Impact Factor
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H Robert Superko,
Kathryn M Momary,
Lakshmana K Pendyala, Paul T Williams,
Steven Frohwein,
Brenda C Garrett,
Cathy Skrifvars,
Radhika Gadesam,
Spencer B King,
Steve Rolader,
Bill Meyers,
David Dusik,
Stoney Polite
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ABSTRACT: To determine the association of cardiovascular risk markers with noninvasive imaging of atherosclerosis in firefighters.
Cross-sectional investigation of subclinical atherosclerosis with metabolic, work related, and life-style variables in 296 professional firefighters.
Calcified coronary atherosclerosis (CAC), carotid arterial intimal thickness (CIMT), and electrocardiogram provided independent CVD assessments. Homeostatic Model Assessment (HOMA) concentrations were related to heart-rate-corrected QT (QTc) (slope ± SE: 2.16 ± 65, P = 0.001), average common CIMT (0.019 ± 0.005 mm, P = 0.0005), and total CAC lesions (0.269 ± 0.116, P = 0.02). Stepwise linear regression selected fasting insulin as the strongest predictor for QTc, HOMA as the strongest predictor of average CIMT, and fasting glucose as the strongest predictor of total coronary lesion number and score.
Firemen's HOMA and fasting insulin and glucose concentrations were significantly associated with three measures of CVD. Aspects of insulin resistance are related to CVD risk among firefighters.
Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 06/2011; 53(7):758-64. · 1.88 Impact Factor
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Paul T Williams
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ABSTRACT: Genetic factors account for 40%-70% of the population variation in body mass index (BMI), suggesting that genetic predisposition is a major risk factor for excess weight. The purpose of this study was to test whether exercise attenuates the inherited risk for excess body weight.
Survey questionnaires of exercise (usual running distance) and BMI were obtained from a national sample of 582 female and 344 male self-identified monozygotic (MZ) twins. Regression analyses were used to test whether running disparity diminished the inheritance of BMI when adjusted for age, education, cigarette use, and selected dietary variables.
The active twins ran between 0 and 10.7 km · d(-1) more than their less active twins if female (mean ± SD = 1.61 ± 1.50 km · d(-1)) and between 0 and 13.7 km · d(-1) more if male (1.88 ± 1.78 km · d(-1)). Average BMIs of the less active twins were 22.38 ± 3.56 and 24.59 ± 3.08 kg · m(-2) in females and males, respectively. Within-twin correlations were significant (P < 0.0001) for usual distance run (females: r = 0.64; males: r = 0.61) and BMI (females: r = 0.67; males: r = 0.71). Greater running differences (Δkm · d(-1)) attenuated the effect of the less active twins' BMIs on their active MZ twins' BMI (females: -14.3% per Δkm · d(-1), P < 10(-7); males: -7.4% per Δkm · d(-1), P = 0.004), such that by 4 Δkm · d(-1), the inherited risk was reduced by 58.8% in females and 29.6% in males.
These results are consistent with the attenuation of the inherited risk of excess body weight by running, which is remarkable because BMI regulation is assumed to be multifactorial, its genetic inheritance is polygenic, and no single genetic polymorphism currently explains >1% of the BMI variance.
Medicine and science in sports and exercise 06/2011; 44(1):98-103. · 3.71 Impact Factor
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ABSTRACT: To assess the relationship of lipoprotein subfractions to coronary heart disease (CHD).
Prospective 29.1-year follow-up of 1905 men measured for lipoprotein mass concentrations by analytic ultracentrifugation between 1954 and 1957. Vital status was determined for 97.2% of the cohort. Blinded physician medical record and death certificate review confirmed 179 CHD deaths. Follow-up questionnaires identified 182 nonfatal myocardial infarctions and 93 revascularization procedures from 1346 (98.3%) of the surviving cohort and from the next-of-kin of 153 men who died.
When adjusted for age, total incident CHD was inversely related to HDL2-mass (P=0.0001) and HDL3-mass (P=0.02), and concordantly related to LDL-mass (P<10(-11)), IDL-mass (P<10(-7)), and small (P<10(-7)) and large VLDL-mass concentrations (P=0.003). The hazard reduction per mg/dl of HDL was greater for HDL2-mass than HDL3-mass (P=0.04). The lowest quartiles of both HDL2-mass (P=0.007) and HDL3-mass (P=0.001) independently predicted total incident CHD when adjusted for traditional risk factors. Risk for premature CHD (≤65 years old) was significantly greater in men within the lowest HDL2 (P=0.03) and HDL3 quartiles (P=0.04) and having higher LDL-mass concentrations (P=0.001). Serum cholesterol's relationship to incident CHD (P<10(-8)) was accounted for by adjustment for LDL-mass concentrations (adjusted P=0.90).
Lipoprotein subfractions differ in their relationship to CHD.
Atherosclerosis 01/2011; 214(1):196-202. · 3.79 Impact Factor
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Paul T Williams
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ABSTRACT: Cardiorespiratory fitness has often been interpreted as a surrogate measurement of physical activity rather than an independent coronary heart disease (CHD) risk factor per se. Fitness is also known to be highly heritable, however, and rats bred selectively for treadmill endurance have low CHD risk phenotypes even in the absence of physical activity. Therefore, I assessed whether cardiorespiratory fitness predicted CHD independent of physical activity in 29,721 men followed prospectively for 7.7 years as part of the National Runners' Health Study. Specifically, CHD deaths and incident participant-reported physician-diagnosed myocardial infarction, revascularization procedures (coronary artery bypass grafting and percutaneous coronary intervention), and angina pectoris during follow-up were compared to baseline cardiorespiratory fitness (10-km footrace performance, meters/second). Nonfatal end points for the 80% of these men who provided follow-up questionnaires included 121 nonfatal myocardial infarctions, 317 revascularization procedures, and 81 angina pectora. The National Death Index identified 44 CHD deaths. Per meter/second increment in baseline fitness, men's risks decreased 54% for nonfatal myocardial infarction (p <0.0001), 44% for combined CHD deaths and nonfatal myocardial infarction (p = 0.0003), 53% for angina pectoris (p = 0.001), and 32% for revascularizations (p = 0.002). Adjustment for physical activity (kilometer/day run) had little effect on the per meter/second risk decreases for nonfatal myocardial infarction (from 64% to 63%), combined CHD deaths and nonfatal myocardial infarction (from 34% to 33%), angina pectoris (from 53% to 47%) or revascularizations (from 32% to 26%). In conclusion, the results suggest that cardiorespiratory fitness is a CHD risk factor, largely independent of physical activity, which warrants clinical screening.
The American journal of cardiology 07/2010; 106(2):210-5. · 3.58 Impact Factor
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Mathew J Barber,
Lara M Mangravite,
Craig L Hyde,
Daniel I Chasman,
Joshua D Smith,
Catherine A McCarty,
Xiaohui Li,
Russell A Wilke,
Mark J Rieder, Paul T Williams,
Paul M Ridker,
Aurobindo Chatterjee,
Jerome I Rotter,
Deborah A Nickerson,
Matthew Stephens,
Ronald M Krauss
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ABSTRACT: Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy.
Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8 x 10(-8)). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0 x 10(-6)). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol.
Using combined GWA analysis from three clinical trials involving nearly 4,000 individuals treated with simvastatin, pravastatin, or atorvastatin, we have identified SNPs that may be associated with variation in the magnitude of statin-mediated reduction in total and LDL-cholesterol, including one in the CLMN gene for which statistical evidence for association exceeds conventional levels of genome-wide significance.
PRINCE and TNT are not registered. CAP is registered at Clinicaltrials.gov NCT00451828.
PLoS ONE 01/2010; 5(3):e9763. · 4.09 Impact Factor
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Kiran Musunuru,
Marju Orho-Melander,
Michael P Caulfield,
Shuguang Li,
Wael A Salameh,
Richard E Reitz,
Göran Berglund,
Bo Hedblad,
Gunnar Engström, Paul T Williams,
Sekar Kathiresan,
Olle Melander,
Ronald M Krauss
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ABSTRACT: Whereas epidemiological studies show that levels of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) predict incident cardiovascular disease (CVD), there is limited evidence relating lipoprotein subfractions and composite measures of subfractions to risk for CVD in prospective cohort studies.
We tested whether combinations of lipoprotein subfractions independently predict CVD in a prospective cohort of 4594 initially healthy men and women (the Malmö Diet and Cancer Study, mean follow-up 12.2 years, 377 incident cardiovascular events). Plasma lipoproteins and lipoprotein subfractions were measured at baseline with a novel high-resolution ion mobility technique. Principal component analysis (PCA) of subfraction concentrations identified 3 major independent (ie, zero correlation) components of CVD risk, one representing LDL-associated risk, a second representing HDL-associated protection, and the third representing a pattern of decreased large HDL, increased small/medium LDL, and increased triglycerides. The last corresponds to the previously described "atherogenic lipoprotein phenotype." Several genes that may underlie this phenotype-CETP, LIPC, GALNT2, MLXIPL, APOA1/A5, LPL-are suggested by SNPs associated with the combination of small/medium LDL and large HDL.
PCA on lipoprotein subfractions yielded three independent components of CVD risk. Genetic analyses suggest these components represent independent mechanistic pathways for development of CVD.
Arteriosclerosis Thrombosis and Vascular Biology 10/2009; 29(11):1975-80. · 6.37 Impact Factor
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Paul T Williams
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ABSTRACT: One-half of Americans currently meet guideline physical activity levels. For these individuals, exceeding guideline levels may provide additional health benefits.
Incident physician-diagnosed myocardial infarction and angina, revascularization procedures (CABG, PTCA), and ischemic heart disease deaths during 7.7-year follow-up were compared to baseline usual distance run in 35,402 male runners.
Men reported 467 incident CHD and the National Death Index identified an additional 54 ischemic heart disease deaths. Per km/day run, the men's risks declined 5% for fatal and nonfatal CHD (P=0.001), nonfatal CHD (P=0.0008), and revascularization procedures (P=0.002). Their risks for nonfatal myocardial infarctions and angina declined 7% (P=0.02) and 10% (P=0.003), respectively. Compared to <3km/day run (upper limit guideline level), >9km/day run produced risks 65% lower for angina (P=0.008), 29% lower for nonfatal CHD (P=0.04), and 26% lower for fatal and nonfatal CHD (P=0.06).
Exceeding guideline physical activity levels produce important CHD-risk reductions.
Atherosclerosis 09/2009; 209(2):524-7. · 3.79 Impact Factor
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ABSTRACT: Although 36% of US men are normal weight (BMI <25 kg/m(2)), the health benefits of greater leanness in normal-weight individuals are seldom acknowledged. To assess the optimal body weight with respect to minimizing coronary heart disease (CHD) risk, we applied Cox proportional hazard analyses of 20,525 nonsmoking, nondiabetic, normal-weight men followed prospectively for 7.7 years, including 20,301 who provided follow-up questionnaires. Two-hundred and forty two men reported coronary artery bypass graph (CABG) or percutaneous transluminal coronary angioplasty (PTCA) and 82 reported physician-diagnosed incident myocardial infarction (267 total). The National Death Index identified 40 additional ischemic heart disease deaths. In these normal-weight men, each kg/m(2) decrement in baseline BMI was associated with 11.2% lower risk for total CHD (P = 0.005), 13.2% lower risk for nonfatal CHD (P = 0.002), 19.0% lower risk for nonfatal myocardial infarction (P = 0.01), and 12.2% lower risk for PTCA or CABG (P = 0.007). Compared to men with BMI between 22.5 and 25 kg/m(2), those <22.5 kg/m(2) had 24.1% lower total CHD risk (P = 0.01), 27.9% lower nonfatal CHD risk (P = 0.01), 37.8% lower nonfatal myocardial infarction risk (P = 0.05), and 27.8% lower PTCA or CABG risk (P = 0.02). In nonabdominally obese men (waist circumference <102 cm), CHD risk declined linearly with declining waist circumference. CHD risk was unrelated to change in waist circumference between 18 years old and baseline except as it contributed to baseline circumference. These results suggest that the optimal BMI for minimizing CHD risk lies somewhere <22.5 kg/m(2), as suggested from our previous analyses of incident diabetes, hypertension, and hypercholesterolemia in these men.
Obesity 07/2009; 17(7):1428-34. · 4.28 Impact Factor
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ABSTRACT: Excess adiposity and high-carbohydrate diets have been associated with an atherogenic lipoprotein phenotype (ALP) characterized by increased concentrations of small, dense low-density lipoprotein (LDL) particles (pattern B). We tested whether weight loss and normalization of adiposity could reverse ALP in overweight men with pattern B. After consuming a moderate-carbohydrate, high-fat diet for 3 weeks, pattern B and nonpattern B (pattern A) men were randomized to a weight loss (n = 60 and n = 36, respectively) or control weight-stable arm (n = 20 and n = 17, respectively). Men in the weight loss arm consumed approximately 1,000 fewer calories per day over 9 weeks to induce an average approximately 9 kg weight loss. In the control group, weight stability was maintained for 4 weeks after randomization. Weight loss led to the conversion of pattern B to pattern A in 58% of baseline pattern B men. Among men who achieved BMIs of <25 kg/m(2) (62% of pattern B men vs. 83% of pattern A men), 81% of pattern B men converted to pattern A. Weight loss was associated with a significantly greater decrease in small, dense LDL subclass 3b in pattern B relative to pattern A men. The lipoprotein profiles of pattern A men who converted from pattern B were comparable to those of men with pattern A at baseline. Conversion of LDL subclass pattern B to pattern A and reversal of ALP can be achieved in a high proportion of overweight men by normalization of adiposity.
Obesity 06/2009; 17(9):1768-75. · 4.28 Impact Factor
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Paul T Williams
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ABSTRACT: The purpose of this study was to assess the dose-response relationship between vigorous physical activity (running distance, km/d) and the participant-reported physician-diagnosed stroke.
Age-adjusted survival analysis of 29 279 men and 12 123 women followed prospectively for 7.7 years.
One hundred men and 19 women reported incident strokes. Per km/d run, the age- and smoking-adjusted risk for stroke decreased 12% in men (P=0.0007), and 11% in men and women combined (P=0.001), which remained significant when further adjusted for baseline diabetes, hypercholesterolemia, hypertension, and BMI (8% and 7% reduction per km/d run, respectively, P=0.03). Men and women who ran >or=2 km/d (ie, exceeded the recommended AHA/CDC and NIH guideline activity level) had significantly lower risk than those who ran less (P=0.05), and those who ran >or=4 km/d had significantly lower risk than those who ran 2 to 3.9 km/d (P=0.02). Men and women who ran >or=8 km/d were at 60% lower risk than those who ran <2 km/d (P=0.00).
The risk for incident stroke is substantially reduced in those who exceed the guideline physical activity level, which cannot be attributed to less hypertension, diabetes, hypercholesterolemia, or body weight.
Stroke 03/2009; 40(5):1921-3. · 5.73 Impact Factor
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Daniel I Chasman,
Guillaume Paré,
Robert Y L Zee,
Alex N Parker,
Nancy R Cook,
Julie E Buring,
David J Kwiatkowski,
Lynda M Rose,
Joshua D Smith, Paul T Williams,
Mark J Rieder,
Jerome I Rotter,
Deborah A Nickerson,
Ronald M Krauss,
Joseph P Miletich,
Paul M Ridker
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ABSTRACT: Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.
We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein(Apo) A1, and ApoB. Genome-wide associations (P < 5 x 10(-8)) were found at the PCSK9 gene, the APOB gene, theLPL gene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus. In addition,genome-wide associations with triglycerides at the GCKR gene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the SORT1 gene. Below genome-wide significance, our study provides confirmatory evidence for associations at 5 novel loci with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB.
Genome-wide associations at the GCKR gene and near the SORT1 gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.
Circulation Cardiovascular Genetics 10/2008; 1(1):21-30. · 6.11 Impact Factor
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Paul T Williams
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ABSTRACT: Benign prostatic hyperplasia (BPH) is generally not considered a preventable condition. Our goal is to assess whether running (a vigorous physical activity) and 10-km race performance (an indicator of cardiorespiratory fitness) reduce BPH risk.
Prospective cohort study of incident BPH in 28,612 nonsmoking, nonvegetarian, nondiabetic men.
The 1899 men (6.64%) reported physician-diagnosed incident BPH during (mean +/- SD) 7.74 +/- 1.84 yr of follow-up. Survival analyses showed significantly lower risk with both longer distance run (km x wk(-1); P < 0.0001) and faster 10-km performance (m x s(-1); P = 0.0004) independent of age, BMI, and meat, fish, fruit, and alcohol intake. When adjusted for age, the fastest men (> or =4.0 m x s(-1)) had 32% lower risk than the slowest men (<3 m x s(-1); P = 0.0006). The decline in incidence extended throughout the performance range, with even the fastest category (> or =4 m x s(-1)) having significantly lower risk than the penultimate fastest category (3.5-4.0 m x s(-1); P = 0.03). The decline in BPH risk with running distance was independent of performance. BPH incidence was more strongly related to the average of the baseline and the follow-up distance run than to concurrent changes in running distance between baseline and follow-up. Incident BPH was significantly lower in men who ran >16 than <16 km x wk(-1) (P = 0.05), >32 than 16-32 km x wk(-1) (P = 0.02), and >48 than 32-48 km x wk(-1) (P = 0.04).
Greater distances run per week may reduce BPH risk independent of BMI, 10-km performance, and diet. If the relationship is causal, then this health benefit accrues at greater exercise doses and intensities than the minimum guideline levels currently recommended.
Medicine and science in sports and exercise 10/2008; 40(10):1733-9. · 3.71 Impact Factor
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Paul T Williams
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ABSTRACT: To estimate the independent relationships of running intensity with antihypertensive, LDL-cholesterol-lowering, and antidiabetic medication use when adjusted for running volume (km x d(-1)).
Self-reported medication use was compared cross-sectionally to running pace (m x s(-1) during usual run) in 25,552 male and 29,148 female National Runners' Health Study participants.
The men ran a mean +/- SD of 5.2 +/- 3.1 km x d(-1) at 3.3 +/- 0.5 m x s(-1) (8.3 +/- 1.4 min x mile(-1)) and the women 4.7 +/- 2.9 km x wk(-1) at 3.0 +/- 0.4 m x s(-1) (9.2 +/- 1.8 min x mile(-1)). When adjusted for kilometers per day, each meter-per-second increment in intensity in men and women reduced the odds for antihypertensive drug use by 54% and 46%, respectively, reduced the odds for LDL-cholesterol-lowering medication use by 55% and 48%, respectively, and reduced the odds for antidiabetic medication use by 50% and 75%, respectively (all P < 0.0001). Compared with men who ran slower than 10 min x mile(-1), the odds for medication use in those who ran or exceeded a 7-min x mile(-1) pace were 72% less for antihypertensive, 78% less for LDL-cholesterol lowering, and 67% less for antidiabetic medications (the corresponding odds reductions in women were 61%, 64%, and 87%, respectively, for 8 min x mile(-1) or faster versus slower than 11 min x mile(-1)). Although usual running pace correlated significantly with a 10-km performance (male, r = 0.55; females, r = 0.49), usual pace remained significantly related to lower use of all three medications in men and antihypertension and antidiabetic medications in women when adjusted for a 10-km performance.
Although these results do not prove causality, they show that exercise intensity is inversely associated with the prevalence of hypertension, hypercholesterolemia, and diabetes independent of exercise volume and cardiorespiratory fitness (10-km performance), suggesting that the more vigorous the exercise, the healthier the health benefits.
Medicine and science in sports and exercise 10/2008; 40(10):1740-8. · 3.71 Impact Factor
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Paul T Williams
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ABSTRACT: To assess whether changes in total and regional adiposity affect the odds for becoming hypercholesterolemic.
Changes in BMI and waist circumference were compared to self-reported physician-diagnosed hypercholesterolemia in 24,397 men and 10,023 women followed prospectively in the National Runners' Health Study.
Incident hypercholesterolemia were reported by 3,054 men and 519 women during (mean +/- s.d.) 7.8 +/- 1.8 and 7.5 +/- 2.0 years of follow-up, respectively. Despite being active, men's BMI increased by 1.15 +/- 1.71 kg/m2 and women's BMI increased by 0.96 +/- 1.89 kg/m2. The odds for developing hypercholesterolemia increased significantly in association with gains in BMI and waist circumferences in both sexes. A gain in BMI > or = 2.4 kg/m2 significantly (P < 0.0001) increased the odds for hypercholesterolemia by 94% in men and 129% in women compared to those whose BMI declined (40 and 76%, respectively, adjusted for average of the baseline and follow-up BMI, P < 0.0001). A gain of > or = 6 cm in waist circumference increased men's odds for hypercholesterolemia by 74% (P < 0.0001) and women's odds by 70% (P < 0.0001) relative to those whose circumference declined (odds increased 40% at P < 0.0001 and 49% at P < 0.01, respectively adjusted for average circumference). BMI and waist circumference at the end of follow-up were significantly associated (P < 0.0001) with the log odds for hypercholesterolemia in both men (e.g., coefficient +/- s.e.: 0.115 +/- 0.011 per kg/m2) and women (e.g., 0.119 +/- 0.019 per kg/m2) when adjusted for baseline values, whereas baseline BMI and circumferences were unrelated to the log odds when adjusted for follow-up values.
These observations are consistent with the hypothesis that weight gain acutely increases the risk for hypercholesterolemia.
Obesity 09/2008; 16(9):2163-8. · 4.28 Impact Factor
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Paul T Williams
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ABSTRACT: Changes in BMI and body size were compared to incident hypertension in 24,550 men and 10,111 women followed prospectively as part of the National Runners' Health Study to test whether long-term weight change affects hypertension risk. Incident hypertensions were reported by 2,143 men and 430 women during (mean +/- s.d.) 7.8 +/- 1.8 and 7.5 +/- 2.0 years of follow-up, respectively. Despite being active, men's and women's BMI increased 1.15 +/- 1.70 and 0.95 +/- 1.89 kg/m(2), respectively, and their waist circumferences increased 2.97 +/- 5.02 and 3.29 +/- 6.67 cm, respectively. Compared to those whose BMI declined, those who gained >or=2.4 kg/m(2) had an odds ratio (95% confidence interval) of 1.68 (1.45, 1.94) for becoming hypertensive if male and 1.42 (1.05, 1.92) if female. Men whose waist circumference increased >or=6 cm had an odds ratio of 1.22 (1.01, 1.47) for becoming hypertensive compared to those whose waists decreased. In both sexes, the odds for hypertension were significantly related to BMI at follow-up when adjusted for baseline BMI, but generally not to baseline BMI when adjusted for follow-up BMI. In the subset whose weights remained relatively unchanged during follow-up (+/-0.4 kg/m(2)), each kg/m(2) increment in BMI was associated with an odds ratio for becoming hypertensive of 1.19 (1.14, 1.24) in men and 1.11 (1.02, 1.20) in women. Thus, even among lean, physically active individuals: (i) weight gain increases hypertension risk; (ii) higher body weight increases the hypertension risk in a dose-dependent manner in the absence of any weight change; and (iii) there is no advantage carried forward to having been previously lean.
Obesity 09/2008; 16(11):2541-8. · 4.28 Impact Factor
