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Matthew R Weir,
Fawn Yeh,
Angela Silverman,
Richard B Devereux,
James M Galloway,
Jeffrey A Henderson,
William J Howard,
Marie Russell,
Charlton Wilson,
Robert Ratner, John Sorkin,
Jason G Umans,
Jerome L Fleg,
Mario Stylianou,
Elisa Lee,
Barbara V Howard
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ABSTRACT: The Stop Atherosclerosis in Native Diabetics Study (SANDS) was a randomized open-label clinical trial in type 2 diabetics designed to examine the effects of intensive reduction of blood pressure, aggressive vs standard goals (< or =115/75 mm Hg vs < or =130/80 mm Hg), and low-density lipoprotein (LDL) cholesterol on the composite outcome of change in carotid intimal-medial thickness and cardiovascular events. The study demonstrated that in conjunction with a lower LDL cholesterol target of 70 mg/dL, aggressive systolic blood pressure-lowering resulted in a reduction in carotid intimal-medial thickness and left ventricular mass without measurable differences in cardiovascular events. The blood pressure treatment algorithm included renin-angiotensin system blockade, with other agents added if necessary. The authors conclude that both standard and more aggressive systolic blood pressure reduction can be achieved with excellent safety and good tolerability in patients with type 2 diabetes mellitus.
Journal of Clinical Hypertension 10/2009; 11(10):540-8. · 1.83 Impact Factor
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Jesse Mez,
John Cole,
Timothy Howard,
Leah MacClellan,
Oscar Stine,
Jeffery O'Connell,
Marcella Wozniak,
Barney Stern, John Sorkin,
Braxton Mitchell,
Steven Kittner
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ABSTRACT: Abstract
Background
Population-based association studies are used to identify common susceptibility variants for complex genetic traits. These studies are susceptible to confounding from unknown population substructure. Here we apply a model-based clustering approach to our case-control study of stroke among young women to examine if self-reported ethnicity can serve as a proxy for genetic ancestry.
Findings
A population-based case-control study of stroke among women aged 15-49 identified 361 cases of first ischemic stroke and 401 age-comparable control subjects. Thirty single nucleotide polymorphisms (SNPs) throughout the genome unrelated to stroke risk and with established ancestry-based allele frequency differences were genotyped in all participants. The Structure program was used to iteratively evaluate for K = 1 to 5 potential genetic-based subpopulations. Evaluating the population as a whole, the Structure output plateaued at K = 2 clusters. 98% of self-reported Caucasians had an estimated probability ≥50% of belonging to Cluster 1, while 94% of self-reported African-Americans had an estimated probability ≥50% of belonging to Cluster 2. Stratifying the participants by self-reported ethnicity and repeating the analyses revealed the presence of two clusters among Caucasians, suggesting that potential substructure may exist.
Conclusions
Among our combined sample of African-American and Caucasian participants there is no large unknown subpopulation and self-reported ethnicity can serve as a proxy for genetic ancestry. Ethnicity-specific analyses indicate that population substructure may exist among the Caucasian participants indicating that further studies are warranted.
BMC Research Notes. 01/2009;
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Braxton D Mitchell,
Patrick F McArdle,
Haiqing Shen,
Evadnie Rampersaud,
Toni I Pollin,
Lawrence F Bielak,
Cashell Jaquish,
Julie A Douglas,
Marie-Hélène Roy-Gagnon,
Paul Sack, [......], John Sorkin,
Coleen M Damcott,
Jeffrey R O'Connell,
Charles Mangano,
Mary Corretti,
Robert Vogel,
William Herzog,
Matthew R Weir,
Patricia A Peyser,
Alan R Shuldiner
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ABSTRACT: The etiology of cardiovascular disease (CVD) is multifactorial. Efforts to identify genes influencing CVD risk have met with limited success to date, likely because of the small effect sizes of common CVD risk alleles and the presence of gene by gene and gene by environment interactions.
The HAPI Heart Study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular risk factors and to identify the genetic and environmental determinants of these responses. The measurements included blood pressure responses to the cold pressor stress test and to a high salt diet, triglyceride excursion in response to a high-fat challenge, and response in platelet aggregation to aspirin therapy.
The interventions were carried out in 868 relatively healthy Amish adults from large families. The heritabilities of selected response traits for each intervention ranged from 8% to 38%, suggesting that some of the variation associated with response to each intervention can be attributed to the additive effects of genes.
Identifying these response genes may identify new mechanisms influencing CVD and may lead to individualized preventive strategies and improved early detection of high-risk individuals.
American heart journal 06/2008; 155(5):823-8. · 4.65 Impact Factor
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ABSTRACT: Self-report measures of physical activity have well-known drawbacks, and physiologic measures alone do not account for behavioral variables important in the perception and performance of physical activity. Therefore, we considered multiple measures to quantify physical activity in community-dwelling men and women with chronic stroke.
This analysis included data from a volunteer sample of 87 individuals at least 6 months poststroke. Physical activity was measured using self-report questionnaires, step activity monitors, self-efficacy expectations related to exercise, and VO(2)peak from treadmill testing, and a model of physical activity was tested.
Most of the variance in objective physical activity was explained by VO(2)peak, and most of the variance in subjective physical activity was explained by self-efficacy expectations. There were significant discrepancies between subjective and objective findings.
This study helps to understand the perspective of stroke survivors with regard to physical activity.
Journal of physical activity & health 04/2008; 5(2):308-18. · 1.95 Impact Factor
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John W Cole,
David W Brown,
Wayne H Giles,
Oscar C Stine,
Jeffrey R O'Connell,
Braxton D Mitchell, John D Sorkin,
Marcella A Wozniak,
Barney J Stern,
Mary J Sparks,
Mark T Dobbins,
Latasha T Shoffner,
Nancy K Zappala,
Laurie J Reinhart,
Steven J Kittner
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ABSTRACT: Although cigarette smoking is a well-established risk factor for vascular disease, the genetic mechanisms that link cigarette smoking to an increased incidence of stroke are not well understood. Genetic variations within the genes of the inflammatory pathways are thought to partially mediate this risk. Here we evaluate the association of several inflammatory gene single nucleotide polymorphisms (SNPs) with ischemic stroke risk among young women, further stratified by current cigarette smoking status.
A population-based case-control study of stroke among women aged 15-49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-comparable control subjects (43.1% African-American). Several inflammatory candidate gene SNPs chosen through literature review were genotyped in the study population and assessed for association with stroke and interaction with smoking status.
Of the 8 SNPs (across 6 genes) analyzed, only IL6 SNP rs2069832 (allele C, African-American frequency = 92%, Caucasian frequency = 55%) was found to be significantly associated with stroke using an additive model, and this was only among African-Americans (age-adjusted: OR = 2.2, 95% CI = 1.0-5.0, p = 0.049; risk factor adjusted: OR = 2.5, 95% CI = 1.0-6.5, p = 0.05). When stratified by smoking status, two SNPs demonstrated statistically significant gene-environment interactions. First, the T allele (frequency = 5%) of IL6 SNP rs2069830 was found to be protective among non-smokers (OR = 0.30, 95% CI = 0.11-.082, p = 0.02), but not among smokers (OR = 1.63, 95% CI = 0.48-5.58, p = 0.43); genotype by smoking interaction (p = 0.036). Second, the C allele (frequency = 39%) of CD14 SNP rs2569190 was found to increase risk among smokers (OR = 2.05, 95% CI = 1.09-3.86, p = 0.03), but not among non-smokers (OR = 0.93, 95% CI = 0.62-1.39, p = 0.72); genotype by smoking interaction (p = 0.039).
This study demonstrates that inflammatory gene SNPs are associated with early-onset ischemic stroke among African-American women (IL6) and that cigarette smoking may modulate stroke risk through a gene-environment interaction (IL6 and CD14). Our finding replicates a prior study showing an interaction with smoking and the C allele of CD14 SNP rs2569190.
Thrombosis Journal 02/2008; 6:11. · 1.31 Impact Factor
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John Cole,
Adam Naj,
Jeffrey O'Connell,
Oscar Stine, John Sorkin,
Marcella Wozniak,
Barney Stern,
Manuel Yepes,
Daniel Lawrence,
Laurie Reinhart,
Dudley Strickland,
Braxton Mitchell,
Steven Kittner
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ABSTRACT: Abstract
Background
Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of neuroserpin polymorphisms with risk for ischemic stroke among young women.
Methods
A population-based case-control study of stroke among women aged 15–49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-matched control subjects (43.1% African-American). Neuroserpin single nucleotide polymorphisms (SNPs) chosen through HapMap were genotyped in the study population and assessed for association with stroke.
Results
Of the five SNPs analyzed, the A allele (frequency; Caucasian = 0.56, African-American = 0.42) of SNP rs6797312 located in intron 1 was associated with stroke in an age-adjusted dominant model (AA and AT vs. TT) among Caucasians (OR = 2.05, p = 0.023) but not African-Americans (OR = 0.71, p = 0.387). Models adjusting for other risk factors strengthened the association. Race-specific haplotype analyses, inclusive of SNP rs6797312, again demonstrated significant associations with stroke among Caucasians only.
Conclusion
This study provides the first evidence that neuroserpin is associated with early-onset ischemic stroke among Caucasian women.
BMC Neurology. 01/2007;
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ABSTRACT: Lifespan is a complex phenotype determined by the interaction of genetic and environmental factors. This makes the identification of variants in genes that influence longevity challenging. We believe that the Old Order Amish (OOA) of Lancaster, Pennsylvania is an excellent population for studying the genetics of longevity. They are a closed population derived from a limited number of founders. They have large families and maintain extensive genealogic records dating to the 1700 s. They eschew modern technology; their lifestyle is little changed over the last 250 years. Homogeneity of environment and lifestyle factors across time and across the OOA population minimizes the influence that environmental factors have in determining the differences in lifespan between individuals. We hypothesize that this reduction in environmental variability will make it easier to identify the genetic factors that influence lifespan. In this article, we describe our strategy for identifying variants in genes that influence longevity in the Amish and present the results of our studies to date.
Mechanisms of Ageing and Development 03/2005; 126(2):347-50. · 3.44 Impact Factor
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ABSTRACT: There are few empirical data to support the claim that weight loss improves coronary heart disease (CHD) risk factors in postmenopausal women; nor is it known if there are racial differences in changes of body fat distribution, lipids, glucose tolerance, and blood pressure with weight loss. This study determined the efficacy of a lifestyle weight loss intervention in reducing total and abdominal obesity and improving CHD risk factors in obese Caucasian and African-American postmenopausal women.
Body composition (dual-energy x-ray absorptiometry), abdominal fat areas (computed tomography scan), lipoprotein lipids, insulin, glucose tolerance, and blood pressure were measured before and after 6 months of hypocaloric diet and low-intensity walking in 76 overweight or obese (body mass index > 25 kg/m(2)), Caucasian (72%) or African-American (28%), postmenopausal (age = 60 +/- 5 years) women who completed the study.
Absolute amount of body weight lost was similar in Caucasians (-5.4 +/- 3.6 kg) and African Americans (-3.9 +/- 3.6 kg), but Caucasian women lost relatively more fat mass (p <.05). Both groups decreased their subcutaneous abdominal fat, and Caucasian women decreased their visceral fat area, but there were no racial differences in the magnitude of abdominal fat lost. The intervention decreased triglyceride and increased high-density lipoprotein and high-density lipoprotein 2 cholesterol in both races, and it decreased total and low-density lipoprotein cholesterol in Caucasian women (p <.05-.0001). Fasting glucose and glucose area during the oral glucose tolerance test decreased (p <.0001) in Caucasian women, whereas insulin area decreased in both Caucasian (p <.01) and African-American (p <.05) women. Blood pressure decreased the most in women with higher blood pressures at baseline. Changes in lipids, fasting glucose and insulin, their responses during the oral glucose tolerance test, and blood pressure were not different between racial groups.
Weight loss achieved through a lifestyle intervention of energy restriction and increased physical activity is an equally effective therapy in African-American and Caucasian obese, postmenopausal women for improving glucose and lipid CHD risk factors.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 02/2003; 58(2):181-9. · 4.60 Impact Factor
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ABSTRACT: 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.
American Journal of Medical Genetics 08/2001; 102(4):346 - 352.
