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.
genetic admixture; African ancestry; fibrinogen; plasmin-antiplasmin; Hispanics; African Americans
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.
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.
Cardiovascular disease; Cardiovascular Health Study; Diabetes; Lipoprotein-associated phospholipase A2; Older adults; Platelet-activating factor acetylhydrolase; Subclinical disease; Type 2 diabetes
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.
aorta; calcium; coronary disease; imaging; risk factors
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.
Aging; Biomarker; Dehydroepiandrosterone sulfate; Function
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.
deep vein thrombosis; venous insufficiency; risk factors; epidemiology; blood coagulation
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.
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.
atherosclerosis; coronary heart disease; tissue factor pathway inhibitor; risk factor
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.
Cerebral infarction; coronary disease; prospective study; protein C; stroke
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.
venous thrombosis; factor XIII; factor VII activating protease; genetics
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.
Albuminuria; Peripheral arterial disease; Epidemiology; Risk factors
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.
Risk factors in epidemiology; intracerebral hemorrhage; cohort studies; incidence studies
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.
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.