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1.  Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study 
Relationships of thrombin generation (TG) with cardiovascular disease risk are under-evaluated in population-based cohorts.
Evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common SNPs and incident cardiovascular disease and stroke.
We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n=5,411), both with and without inhibitory anti-FXIa antibody (pTG/FXIa−). We evaluated their associations with ~50K SNPs using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2-years.
The minor allele for a SNP in the coagulation factor XII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β=−34.2 nM ± 3.5 nM; p=3.3×10−22; minor allele frequency (MAF) =0.23) and African-Americans (β=−31.1 nM ± 7.9 nM; p=9.0×10−5; MAF=0.42). Lower FXIa-independent pTG (pTG/FXIa−) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa− was associated with the ABO SNP rs657152 minor allele (β=16.3 nM; p=4.3×10−9; MAF=0.37). The risk factor-adjusted ischemic stroke hazard ratio (95% confidence interval) was 1.09 (1.01, 1.17; p=0.03) for pTG, 1.06 (0.98, 1.15; p=0.17) for pTG/FXIa−, and 1.11 (1.02, 1.21; p=0.02) for FXIa-dependent pTG (pTG/FXIa+), per 1-SD increment (n=834 ischemic strokes). In a multi-cohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β= −0.02; (SE=0.08); p=0.81).
These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke and indicate the importance of F12 SNPs on TG ex vivo and in vivo.
PMCID: PMC4946166  PMID: 26286125
Cardiovascular Diseases; Epidemiology; Factor XIIa; Single Nucleotide Polymorphisms; Thrombin
2.  Prospective study of sickle cell trait and venous thromboembolism incidence 
Sickle cell trait may increase risk of venous thromboembolism, but this is not fully established.
We sought to determine the association of sickle cell trait with deep vein thrombosis and pulmonary embolism.
Middle-aged African Americans participating in a prospective, population-based cohort investigation, the Atherosclerosis Risk in Communities Study, were followed from 1987 through 2011 for incident hospitalized pulmonary embolism (n = 111) or isolated deep vein thrombosis (n = 138), verified by physician review of medical records. Sickle cell trait (heterozygosity for hemoglobin S, n = 268) was compared with no sickle cell trait (n = 3,748).
Over a median of 22 years of follow-up, 249 participants had an incident venous thromboembolism. The hazard ratio of venous thromboembolism was 1.50 (95% CI 0.96, 2.36) for participants with versus without sickle cell trait, after adjustment for age, sex, ancestry, hormone replacement therapy (women), body mass index, diabetes, and estimated glomerular filtration rate. This hazard ratio was 2.05 (95% CI 1.12, 3.76) for pulmonary embolism and 1.15 (95% CI 0.58, 2.27) for deep vein thrombosis without pulmonary embolism.
Sickle cell trait in African Americans carries a 2-fold increased risk of pulmonary embolism, but does not elevate deep vein thrombosis risk. Because neonatal screening for sickle hemoglobin is being conducted in the United States currently, consideration should be paid to the increased pulmonary embolism risk of individuals with sickle cell trait.
PMCID: PMC4294976  PMID: 25393788
epidemiology; prospective study; risk factors; sickle cell trait; venous thromboembolism
3.  Development and validation of an ankle brachial index risk model for the prediction of cardiovascular events 
The ankle brachial index (ABI) is related to risk of cardiovascular events independent of the Framingham risk score (FRS). The aim of this study was to develop and evaluate a risk model for cardiovascular events incorporating the ABI and FRS.
An analysis of participant data from 18 cohorts in which 24,375 men and 20,377 women free of coronary heart disease had ABI measured and were followed up for events.
Subjects were divided into a development and internal validation dataset and an external validation dataset. Two models, comprising FRS and FRS + ABI, were fitted for the primary outcome of major coronary events.
In predicting events in the external validation dataset, C-index for the FRS was 0.672 (95% CI 0.599 to 0.737) in men and 0.578 (95% CI 0.492 to 0.661) in women. The FRS + ABI led to a small increase in C-index in men to 0.685 (95% CI 0.612 to 0.749) and large increase in women to 0.690 (95% CI 0.605 to 0.764) with net reclassification improvement (NRI) of 4.3% (95% CI 0.0 to 7.6%, p = 0.050) and 9.6% (95% CI 6.1 to 16.4%, p < 0.001), respectively. Restricting the FRS + ABI model to those with FRS intermediate 10-year risk of 10 to 19% resulted in higher NRI of 15.9% (95% CI 6.1 to 20.6%, p < 0.001) in men and 23.3% (95% CI 13.8 to 62.5%, p = 0.002) in women. However, incorporating ABI in an improved newly fitted risk factor model had a nonsignificant effect: NRI 2.0% (95% CI 2.3 to 4.2%, p = 0.567) in men and 1.1% (95% CI 1.9 to 4.0%, p = 0.483) in women.
An ABI risk model may improve prediction especially in individuals at intermediate risk and when performance of the base risk factor model is modest.
PMCID: PMC4685459  PMID: 24367001
Ankle brachial index; cardiovascular diseases; risk assessment
4.  Serum 25-hydroxyvitamin D and risk of venous thromboembolism: The Atherosclerosis Risk in Communities (ARIC) Study 
Some evidence suggests that an inadequate vitamin D level may increase the risk atherosclerotic cardiovascular disease. Whether low vitamin D has a role in venous thromboembolism (VTE), i.e., venous thrombosis and pulmonary embolism, is largely unexplored.
We tested prospectively in the Atherosclerosis Risk in Communities (ARIC) cohort whether the serum concentration of 25-hydroxyvitamin D (25(OH)D) is inversely associated with VTE incidence and whether it partly explains the African American excess of VTE in ARIC.
Patients and Methods
We measured 25(OH)D using mass spectroscopy in stored samples of 12,752 ARIC study participants and followed them over a median of 19.7 years (1990-92 through 2011) for incidence of VTE (n = 537).
The seasonally-adjusted 25(OH)D concentration was not associated with VTE incidence. In a model adjusted for age, race, sex, hormone replacement therapy, and body mass index, the hazard ratios of VTE across 25(OH)D quintiles 5 (high) to 1 (low) were: 1 (Ref.), 0.84 (0.65, 1.08), 0.88 (0.68, 1.13), 1.04 (0.78, 1.38), and 0.90 (0.64, 1.27). The lowest 25(OH)D quintile comprised 59% African Americans, whereas the highest quintile comprised 7% African Americans. Yet, lower 25(OH)D concentrations explained little of the 63% greater VTE risk of African Americans over whites in this cohort.
Low 25(OH)D was not a risk factor for VTE in this prospective study. Yet, the totality of literature (three studies) suggests that low 25(OH)D might modestly increase VTE risk in whites, but this needs further confirmation.
PMCID: PMC4163112  PMID: 25039645
Prospective studies; pulmonary embolism; risk factors; venous thrombosis; vitamin D
5.  Glycemia (hemoglobin A1c) and incident venous thromboembolism in the Atherosclerosis Risk in Communities Cohort Study 
Diabetes has been inconsistently associated with increased risk of venous thromboembolism (VTE) and there is little direct evidence on associations of glycemia levels with VTE. We used data from the Atherosclerosis Risk in Communities Study to test the hypothesis that glycemia, as measured by hemoglobin A1c (A1c), is positively associated with VTE.
Participants aged 45 to 64 years (n=12,298) had A1c measured in 1990 and were followed for incident VTE (n=345) through 2005. Because A1c is affected by diabetes treatment, analyses were stratified by history of diagnosed diabetes. Due to evidence of nonlinearity, we categorized A1c according to clinical cut-points: <5.7, 5.7-6.4, and ≥6.5% in those with no diagnosed diabetes; and <7.0 and ≥7.0% in those with diagnosed diabetes.
After adjustment for potential confounders, the hazard ratios (95% CIs) for VTE across increasing A1c categories were 1 (referent), 1.02 (0.77, 1.35) and 0.72 (0.41, 1.29) for those without diagnosed diabetes, and 1.30 (0.77, 2.17), and 1.41 (0.95, 2.09) for those with diagnosed diabetes. To explore the relation, we employed various models to adjust for potential confounding variables and modeled A1c as tertiles. We consistently found elevated HRs in those with diagnosed diabetes, though the association was not statistically significant in every model. HRs in those without diagnosed diabetes were close to 1.
Our results are mildly suggestive that diagnosed diabetes and high levels of glucose, per se, may increase the risk of VTE. Elevated glucose was not related to VTE in those without diagnosed diabetes.
PMCID: PMC3980470  PMID: 24165467
Epidemiology; venous thrombosis; pulmonary embolism; glucose, blood; diabetes mellitus; risk factors
6.  Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls 
European journal of epidemiology  2013;28(8):621-647.
Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden,FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies.
We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR).
We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95% confidence intervals [CI]: 0.98–1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR=4.22; 95% CI: 3.35–5.32; and OR=2.79;95% CI: 2.25–3.46, respectively), in double hterozygotes (OR=3.42; 95%CI 1.64-7.13), and in homozygous FVL or PT20210A (OR=11.45; 95%CI: 6.79-19.29; and OR: 2.79; 95%CI: 2.25 – 3.46, respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤45 years (p-value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045).
In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.
PMCID: PMC3935237  PMID: 23900608
Venous thromboembolism; genetic susceptibility; Factor V Leiden; Prothrombin G202010A; Methylentetrahydrofolate reductase C677T
7.  Phase I Study of Capecitabine, Oxaliplatin, Bevacizumab, and Everolimus in Advanced Solid Tumors 
Investigational new drugs  2014;32(4):700-709.
To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients.
This was a standard “3+3” dose-escalation trial. All subjects received bevacizumab 7.5mg/kg on day one of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms.
Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; eight of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival.
Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5mg daily; capecitabine 680mg/m2 BID days 1-14; oxaliplatin 100mg/m2 and bevacizumab 7.5mg/kg, day one. Activity was noted in mCRC.
PMCID: PMC4103954  PMID: 24711126
Capecitabine; Oxaliplatin; Bevacizumab; Everolimus; Phase I; Advanced Cancer
8.  The relationship between inflammation, obesity and risk for hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Journal of human hypertension  2010;25(2):73-79.
It has been suggested that inflammation is important in the aetiology of hypertension and that this may be most relevant among obese persons. To study this, we examined the independent relationships between obesity, inflammation-related proteins (interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen) and risk for hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA). Hypertension status, defined as a blood pressure ≥140/90 mm Hg or a history of hypertension and use of blood pressure medications, was determined at baseline and two subsequent exams over 5 years. Among 3543 non-hypertensives at baseline, 714 individuals developed incident hypertension by Exam 3. Cox proportional hazard models were used to determine the relationship between baseline levels of IL-6, CRP and fibrinogen and future risk of hypertension. One s.d. difference in baseline concentration of IL-6, CRP or fibrinogen was associated with 20–40% greater risk of incident hypertension. This risk was attenuated after accounting for other hypertension risk factors (hazard ratio (HR) IL-6: 1.13 (95% CI: 1.04–1.23); CRP: 1.11 (95% CI: 1.02–1.21); fibrinogen 1.0 (95% CI: 0.92–1.08)). Conversely, obesity was an independent risk factor for hypertension risk, minimally impacted by other covariates, including IL-6 and CRP (HR 1.72 (95% CI: 1.36–2.16)). IL-6 and CRP did not modify the relationship between obesity and hypertension, though an adjusted twofold greater risk was observed for obese individuals with a CRP >3 mg l−1 compared with CRP <1 mg l−1. The relationship between inflammation-related proteins and hypertension risk was predominantly explained by other hypertension risk factors. Obesity, independent of inflammation, remained a potent risk factor for future hypertension.
PMCID: PMC4066617  PMID: 20944659
inflammation; obesity; blood pressure
9.  Genetic admixture is associated with plasma hemostatic factor levels in self-identified African Americans and Hispanics: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Epidemiologic studies report that self-identified African Americans typically have higher hemostatic factor levels than do self-identified Caucasians or Hispanics.
To better understand phenotypic variation in hemostatic factor levels by race/ethnicity we evaluated the relationship between genetic ancestry and hemostatic factor levels among MESA study participants.
Our sample included 712 African American and 701 Hispanic men and women aged 45–84. Individual global ancestry was estimated from 199 genetic markers using STRUCTURE. Linear regression models were used to evaluate the relationship between ancestry and hemostatic factor levels, adjusting for age, sex, education, income, and study site.
Among African Americans, mean±SD ancestry was estimated as 79.9% ± 15.9% African and 20.1% ± 15.9% European. Each SD (16%) greater African ancestry was associated with 2.1% higher fibrinogen levels (p=0.007) and 3.5% higher plasmin-antiplasmin (PAP) levels (p=0.02). Ancestry among African Americans was not related to levels of factor VIII or D-Dimer. Mean±SD estimated ancestry among Hispanics was 48.3% ± 23.8% Native American, 38.8% ± 21.9% European, and 13.0% ±18.9% African. In Hispanics, each SD (19%) greater African ancestry was associated with 2.7% higher fibrinogen levels (p=0.009) and 7.9% higher factor VIII levels (p=0.0002). In Hispanics, there was no relation between African ancestry and D-dimer or PAP levels, or between European ancestry and hemostatic factor levels.
Greater African ancestry among African Americans and Hispanics was associated with higher levels of several hemostatic factors, notably fibrinogen. These results suggest that genetic heterogeneity contributes, albeit modestly, to racial/ethnic differences in hemostatic factor levels.
PMCID: PMC3361899  PMID: 22332961
genetic admixture; African ancestry; fibrinogen; plasmin-antiplasmin; Hispanics; African Americans
10.  Vascular risk factors and cognitive impairment in a stroke-free cohort 
Neurology  2011;77(19):1729-1736.
To examine vascular risk factors, as measured by the Framingham Stroke Risk Profile (FSRP), to predict incident cognitive impairment in a large, national sample of black and white adults age 45 years and older.
Participants included subjects without stroke at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with at least 2 cognitive function assessments during the follow-up (n = 23,752). Incident cognitive impairment was defined as decline from a baseline score of 5 or 6 (of possible 6 points) to the most recent follow-up score of 4 or less on the Six-item Screener (SIS). Subjects with suspected stroke during follow-up were censored.
During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment. Baseline FSRP score was associated with incident cognitive impairment. An adjusted model revealed that male sex (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.43–1.77), black race (OR = 2.09, 95% CI 1.88–2.35), less education (less than high school graduate vs college graduate, OR = 2.21, 95% CI 1.88–2.60), older age (10-year increments, OR = 2.11, per 10-year increase in age, 95% CI 2.05–2.18), and presence of left ventricular hypertrophy (LVH, OR = 1.29, 95% CI 1.06–1.58) were related to development of cognitive impairment. When LVH was excluded from the model, elevated systolic blood pressure was related to incident cognitive impairment.
Total FSRP score, elevated blood pressure, and LVH predict development of clinically significant cognitive dysfunction. Prevention and treatment of high blood pressure may be effective in preserving cognitive health.
PMCID: PMC3208949  PMID: 22067959
11.  Lipoprotein-associated phospholipase A2 and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study 
Diabetologia  2010;54(2):329-333.
Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA2 levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.
We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA2 mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.
At baseline, Lp-PLA2 mass did not differ significantly by type 2 diabetes status; however, Lp-PLA2 activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA2 (OR 1.68 [95% CI 1.31–2.15] vs OR 1.67 [95% CI 1.30–2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA2 activity.
In this older cohort, differences in Lp-PLA2 activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.
PMCID: PMC3489174  PMID: 21103980
Cardiovascular disease; Cardiovascular Health Study; Diabetes; Lipoprotein-associated phospholipase A2; Older adults; Platelet-activating factor acetylhydrolase; Subclinical disease; Type 2 diabetes
12.  Risk Factor Differences for Aortic vs. Coronary Calcified Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis 
To compare and contrast coronary artery calcium (CAC) with abdominal aortic calcium (AAC) in terms of their associations with traditional and novel cardiovascular disease (CVD) risk factors.
Methods and Results
We measured both AAC and CAC using computed tomography (CT) scans in 1974 men and women aged 45–84 years from a multi-ethnic cohort. Traditional and novel CVD risk factors were examined separately in relation to AAC and CAC, employing logistic regression for qualitative categorical comparisons and multiple linear regression for quantitative continuous comparisons. AAC was significantly associated with cigarette smoking and dyslipidemia, and showed no gender difference. In contrast, CAC showed much weaker associations with smoking and dyslipidemia, and a strong male predominance. Age and hypertension were associated similarly and significantly with AAC and CAC. Novel risk factors generally showed no independent association with either calcium measure, although in subset analyses phosphorous, but not calcium, was related to CAC. The ROC curves for the qualitative results and the r-squared values for the quantitative analyses were both much higher for AAC than for CAC.
AAC showed stronger correlations with most CVD risk factors than did CAC. The predictive value of AAC compared to CAC for incident CVD events remains to be evaluated.
PMCID: PMC2959146  PMID: 20814018
aorta; calcium; coronary disease; imaging; risk factors
13.  Concurrent Change in Dehydroepiandrosterone Sulfate and Functional Performance in the Oldest Old: Results From the Cardiovascular Health Study All Stars Study 
The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging.
DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996–1997 and 2005–2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005–2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline.
After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline.
In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.
PMCID: PMC2920580  PMID: 20466773
Aging; Biomarker; Dehydroepiandrosterone sulfate; Function
14.  Risk factors for peripheral venous disease resemble those for venous thrombosis: the San Diego Population Study 
Clinically silent deep vein thrombosis (DVT) is common and may cause chronic venous disease that resembles post-thrombotic syndrome.
We evaluated whether peripheral venous disease in a general population shares risk factors with DVT.
In an established cohort of 2,404 men and women, the San Diego Population Study, peripheral venous disease was evaluated using physical exam, symptom assessment, and venous ultrasound. We performed a case control study including 308 cases in 4 hierarchical groups by severity, and 346 controls without venous abnormalities, frequency matched to cases by 10-year age group, race and sex. Cases and controls had no prior history of venous thrombosis. Hemostatic risk factors were measured in cases and controls.
Accounting for age, obesity and family history of leg ulcer, ORs for elevated factor VIII, von Willebrand factor, D-dimer, and for factor V Leiden were 1.4 (95% CI 0.9–2.1), 1.5 (CI 1.0–2.3), 1.7 (CI 1.1–2.8), and 1.1 (CI 0.5–2.4), respectively. These associations were larger in the two most severe case groups; ORs 2.0 (CI 1.0–3.8), 1.7 (CI 0.9–3.3), 2.7 (CI 1.2–6.1) and 2.3 (CI 0.8–7.1). Each hemostatic factor was also associated with severity of venous disease, for example elevated D-dimer was associated with a 2.2-fold increased odds of being in one higher severity group. Prothrombin 20210A was not associated with venous disease.
DVT risk factors are associated with presence and severity of peripheral venous disease. Results support a hypothesis that peripheral venous disease may sometimes be post-thrombotic syndrome due to previous unrecognized DVT.
PMCID: PMC2937057  PMID: 20492466
deep vein thrombosis; venous insufficiency; risk factors; epidemiology; blood coagulation
15.  Fibrinogen and IL6 Gene Variants and IL-6 Levels in Relation to Plasma Fibrinogen Concentration and Cardiovascular Disease Risk in the Cardiovascular Health Study 
Annals of human genetics  2010;74(1):1-10.
The inflammatory cytokine interleukin-6 (IL-6) is a main regulator of fibrinogen synthesis, though its interaction with fibrinogen genes (FGA, FGB, FGG) in relation to CVD risk is not well-studied in humans.
Methods and Results:
We investigated joint associations of common fibrinogen and IL6 tagSNPs with fibrinogen level, carotid intima-media thickness (IMT) and risk of myocardial infarction (MI) or ischemic stroke in 3900 European-American participants of the Cardiovascular Health Study. To identify combinations of genetic main effects and interactions associated with each outcome, we used logic regression. We also evaluated whether the relationship between fibrinogen SNPs and fibrinogen level varied by IL-6 level using linear regression models with multiplicative interaction terms. Combinations of fibrinogen and IL6 SNPs were associated with fibrinogen level (p<0.005), but not with IMT (p>0.30), MI (p=0.73) or stroke (p=0.21). Fibrinogen levels were higher in higher in individuals having FGB1437 (rs1800790) minor alleles and lacking FGA6534 (rs6050) minor alleles; these SNPs interacted with IL6 rs1800796 to influence fibrinogen level. Marginally significant (p=0.03) interactions between IL-6 level and SNPs located in promoter regions of FGA and FGG associated with fibrinogen levels were detected.
We identified potential gene-gene interactions influencing fibrinogen levels. Although IL-6 responsive binding sites are present in fibrinogen gene promoter regions, we did not find strong evidence of interaction between fibrinogen SNPs and IL6 SNPs or levels influencing CVD risk.
PMCID: PMC2946374  PMID: 20059469
16.  Tissue factor pathway inhibitor, vascular risk factors and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;207(1):277-283.
Tissue factor pathway inhibitor (TFPI) is an endothelial membrane-associated anticoagulant protein. Higher circulating levels might reflect endothelial damage.
We hypothesized an association of higher total TFPI with subclinical atherosclerosis.
Total TFPI was measured in 1000 participants of the Multi-Ethnic Study of Atherosclerosis, a cohort of 6814 men and women without clinical vascular disease, aged 45–84, from 4 ethnic groups. Subclinical atherosclerosis measures were coronary artery calcium (CAC), carotid intima-media thickness (IMT) and ankle-brachial index (ABI).
TFPI was higher with age, male gender, higher LDL-cholesterol, smoking and diabetes, but not ethnicity. Adjusting for risk factors, TFPI in the 4th versus 1st quartile was associated with a 1.2-fold increased risk of detectable CAC (95% CI 1.0–1.4), a 2.1-fold increased risk of CAC >400 Agatston units (95% CI 1.1–4.0) and a 1.6-fold (95% CI 1.1–2.5) increased risk of internal carotid IMT above the 80th percentile, but not with external carotid IMT or low ABI. Findings were consistent across ethnic groups.
In this diverse population, higher total TFPI was associated with prevalent CAC (limited to levels >400 units), and elevated internal carotid IMT, independent of other factors. Higher TFPI may indicate endothelial dysfunction. Further study is needed of TFPI and progression of atherosclerosis.
PMCID: PMC2784263  PMID: 19467658
atherosclerosis; coronary heart disease; tissue factor pathway inhibitor; risk factor
17.  Low protein C and incidence of ischemic stroke and coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) Study 
Protein C is an important plasma natural anticoagulant. Although protein C deficiency increases risk of venous thrombosis, it remains uncertain whether low protein C increases risk of atherothrombosis.
To examine whether low protein C may be a risk factor for ischemic stroke or coronary events in a prospective population-based study.
The Atherosclerosis Risk in Communities Study assessed protein C antigen by ELISA at baseline in 1987–89 and followed participants (n=13,879) for incident ischemic stroke or coronary events through 2005.
Over a median of 16.9 years of follow-up, 613 ischemic strokes and 1,257 coronary heart disease events occurred. Protein C was inversely associated with incidence of ischemic stroke. Adjusted for multiple risk factors, the rate ratios (95% CIs) from highest to lowest quintiles were 1.0, 1.16 (0.90–1.50), 1.22 (0.94–1.58), 1.18 (0.90–1.55), and 1.52 (1.17–1.98). This inverse association was stronger for nonlacunar and cardioembolic stroke than for lacunar stroke. In contrast, there was a positive association between protein C and coronary heart disease in incompletely adjusted models, but no association after adjustment for plasma lipids.
In this cohort study, low protein C was a risk factor for incident ischemic stroke but not coronary heart disease. Levels of protein C associated with stroke risk were not restricted to the traditional ‘deficient’ range for protein C (<0.5 percentile), suggesting that other etiologies for a lower protein C, or genetic variants associated with more subtle changes in protein C, are playing a role in disease pathogenesis.
PMCID: PMC2819378  PMID: 19691480
Cerebral infarction; coronary disease; prospective study; protein C; stroke
18.  Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study 
Age-related changes in blood coagulation and fibrinolysis are associated with increased risk of thrombotic events. Inherited deficiencies of coagulation proteins, such as factor V Leiden and prothrombin G20210A, explain a small fraction of venous thromboembolic disease (VTE). Additional genetic factors likely underlie the etiology of VTE, some of which may become manifest at older ages.
We tested 290 common SNPs within 51 thrombosis and inflammation genes for association with VTE in the Cardiovascular Health Study, a large, prospective cohort of older adults followed for up to 12 years.
There were 184 VTE events that occurred at mean age of 78 years. TagSNPs within four genes encoding factor XIII subunit A (F13A), factor VII activating protease (HABP2), protease activated receptor -1 (F2R), and the urokinase receptor (PLAUR) showed the strongest evidence for association with VTE, with each gene having a global p-value <0.05 and at least one tagSNP false discovery rate (FDR) q-value <0.05. The rs3024409 variant allele of F13A1 was associated with 1.66-fold increased risk of VTE, while the minor alleles of HABP2 rs6585234 and rs3862019, F2R rs253061 and rs153311, and PLAUR rs344782 were each associated with lower risk of VTE (hazard ratios in the range of 0.49 to 0.66). Consistent with the observed protective association on VTE risk, the HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors VIII, IX, X, and plasminogen. We also confirm previously reported associations between common variants of the coagulation factor II, V, VIII, XI, alpha-fibrinogen, and protein C genes and risk of VTE.
These findings suggest that several novel common coagulation gene variants may be related to risk of VTE in older adults. Further studies in older adults are needed to validate these findings and assess functional molecular mechanisms.
PMCID: PMC2853009  PMID: 19552680
venous thrombosis; factor XIII; factor VII activating protease; genetics
19.  Albuminuria and peripheral arterial disease: Results from the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2008;201(1):212-216.
The association of albuminuria with cardiovascular disease (CVD) is increasingly recognized, but its association with peripheral arterial disease (PAD) is not well characterized in subjects with or without diabetes.
Using data from the Multi-Ethnic Study of Atherosclerosis, a cohort free of clinical vascular disease, we analyzed the cross-sectional association between albuminuria and PAD in diabetic and nondiabetic subjects. A spot urine albumin-creatinine ratio (ACR) was used to define albuminuria in two ways: presence or absence of albuminuria and the degree of albuminuria (no albuminuria defined as urine ACR < 17 mg/g for men and < 25 mg/g for women, microalbuminuria as urine ACR 17 to 249 mg/g for men and 25 to 334 mg/g for women, and macroalbuminuria as urine ACR ≥ 250 mg/g for men and ≥ 355 mg/g for women). PAD was defined by ankle-brachial index (ABI) < 0.9.
Among the 6,760 subjects, aged 45-84 years, 326 (4.8%) had prevalent PAD. 813 (12.0%) subjects had microalbuminuria and 100 (1.5%) had macroalbuminuria. Among diabetic subjects, those with albuminuria (micro and macroalbuminuria combined) were 1.90 times more likely to have PAD (95% CI: 1.19-3.04) than those with no albuminuria. After adjusting for CVD risk factors, the odds ratio modestly attenuated to 1.65 (95% CI: 1.00-2.74). For nondiabetic subjects, there were no statistically significant associations observed in the univariable and multivariable analyses. The degree of albuminuria was not associated with PAD in either diabetic or nondiabetic subjects.
The presence, but not magnitude of albuminuria, is an important risk factor for PAD in diabetic but not in nondiabetic subjects.
PMCID: PMC2783891  PMID: 18281047
Albuminuria; Peripheral arterial disease; Epidemiology; Risk factors
20.  Hemostatic and Inflammatory Risk Factors for Intracerebral Hemorrhage in a Pooled Cohort 
Background and Purpose
To identify novel risk factors for intracerebral hemorrhagic stroke (ICH)
Risk factors were assessed at baseline in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), involving 21,680 adults, aged 45 or over. Over 263,489 person-years of follow-up, we identified 135 incident ICH events.
In multivariable models, for each standard deviation higher baseline level of fibrinogen the relative rate of incident ICH increased 35% (95% CI 17%−55%). Fibrinogen was more strongly related to ICH in ARIC than in CHS. In multivariable models those with von Willebrand factor (vWF) levels above the median were 1.72 (95% CI 0.97−3.03) times more likely to have an incident ICH as those below the median. Factor VIII was significantly positively related to ICH in ARIC (relative rate per standard deviation of 1.31, 95% CI 1.07−1.62), but not in CHS. There was no relation in multivariable models between Lp(a), factor VII, white blood cell count, or C-reactive protein and ICH.
Greater plasma fibrinogen, and to some degree vWF, were associated with increased rates of ICH in these prospective studies, while factor VIII was related to ICH in younger ARIC study participants only.
PMCID: PMC2578823  PMID: 18535282
Risk factors in epidemiology; intracerebral hemorrhage; cohort studies; incidence studies
21.  Incidence and predictors of coronary heart disease among older African Americans--the Cardiovascular Health Study. 
Although coronary heart disease (CHD) is the leading cause of death and morbidity in older African Americans, relatively little is known about the incidence and predictors of CHD in this population. This study was undertaken to determine the incidence and predictors of CHD in African-American men and women aged 65 years and older. The participants in this study included a total of 924 African-American men and women aged 65 years of age and older who participated in the Cardiovascular Health Study (CHS). The overall CHD incidence was 26.6 per 1,000 person-years of risk. Rates were higher in men than women (35.3 vs. 21.6) and in those 75 years or older than in those less than 75 years (31.3 vs. 24.5). In multivariate analysis, factors associated with higher risk of incident disease were male gender [relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.1, 2.7], diabetes mellitus (RR = 1.9, 95% CI = 1.2, 2.9), total cholesterol (RR for 40 mg/dL increment = 1.3, 95% CI = 1.0, 1.5), and low (i.e., <0.9) ankle-arm index (RR = 2.1, 95% CI = 1.3, 3.4) after adjusting for age. Within this cohort of older African Americans, male gender, diabetes mellitus, total cholesterol, and low ankle-arm index and were independently predictive of incident events. These results suggest that the ankle-arm index, a measure of advanced atherosclerosis, should be further evaluated for its efficacy in identifying older African Americans at risk for incident clinical events.
PMCID: PMC2594007  PMID: 11730114
22.  Production and antibacterial activity of malforming C, a toxic metabolite of Aspergillus niger. 
The production of the new mycotoxin malformin C by a solid substrate fermentation is described. Malformin C is highly toxic (mean lethal dose = 0.9 mg/kg) and exerts antibacterial activity against a variety of gram-positive and gram-negative organisms.
PMCID: PMC170807  PMID: 869543

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