Reproductive events may affect the onset of chronic diseases. We examined the possible association between reproductive parameters and intima media thickness (IMT) or carotid plaques in the common carotid artery in a population-based sample.
This cross-sectional study analysed data of 800 postmenopausal women aged 50 to 81 years of the population-based KORA F4 study, conducted between 2006 and 2008 in Southern Germany. Reproductive parameters were obtained by standardised interviews.
Age at menarche below 12 years compared to 12-15 years was significantly associated with carotid plaques (age-adjusted OR 2.23, 95% CI 1.13-4.43, p-value 0.018, multivariable adjusted 2.11, 1.05-4.26, 0.037), but not with IMT. Ever use of hormone replacement therapy was inversely associated with carotid plaques (age-adjusted 0.60, 0.44-0.81, p = 0.001, multivariable-adjusted 0.62, 0.45-0.86, 0.003) and IMT in the age-adjusted model (mean 0.89, 95% CI 0.88-0.90, p = 0.033) but not in the multivariable-adjusted model (mean 0.89, 95% CI 0.88-0.90, p = 0.075). Parity, age at menopause, time since menopause, duration of fertile period, current use of hormone replacement therapy, ever use of oral contraceptives, hysterectomy, bilateral oophorectomy, hot flashes and depressive mood in relation to the menopausal transition were not associated with carotid plaques or IMT.
Our study showed, that there may be an independent association between the reproductive parameters age at menarche and ever use of hormone replacement therapy with carotid plaques in the common carotid artery, but not with IMT. Further research, especially in studies with prospective population-based study design, is necessary to assess in detail what events in women’s life lead to increased IMT or CP.
Intima media thickness; Atherosclerosis; Cardiovascular disease; Women; Reproductive factors; Gender studies
Current guidelines recommend measuring plasma lipids in fasting patients. Recent studies, however, suggest that variation in plasma lipid concentrations secondary to fasting time may be minimal. Objective of the present study was to investigate the impact of fasting time on plasma lipid concentrations (total cholesterol, HDL and LDL cholesterol, triglycerides). A second objective was to determine the effect of non-alcoholic fatty liver disease exerted on the above-mentioned lipid levels.
Subjects participating in a population-based cross-sectional study (2,445 subjects; 51.7% females) were questioned at time of phlebotomy regarding duration of pre-phlebotomy fasting. Total cholesterol, LDL and HDL cholesterol, and triglycerides were determined and correlated with length of fasting. An upper abdominal ultrasonographic examination was performed and body-mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Subjects were divided into three groups based on their reported fasting periods of 1–4 h, 4–8 h and > 8 h. After application of the exclusion criteria, a total of 1,195 subjects (52.4% females) were included in the study collective. The Kruskal-Wallis test was used for continuous variables and the chi-square test for categorical variables. The effects of age, BMI, WHR, alcohol consumption, fasting time and hepatic steatosis on the respective lipid variables were analyzed using multivariate logistic regression.
At multivariate analysis, fasting time was associated with elevated triglycerides (p = 0.0047 for 1–4 h and p = 0.0147 for 4–8 h among females; p < 0.0001 for 1–4 h and p = 0.0002 for 4–8 h among males) and reduced LDL cholesterol levels (p = 0.0003 for 1–4 h and p = 0.0327 for 4–8 h among males). Among males, hepatic steatosis represents an independent factor affecting elevated total cholesterol (p = 0.0278) and triglyceride concentrations (p = 0.0002).
Total and HDL cholesterol concentrations are subject to slight variations in relation to the duration of the pre-phlebotomy fasting period. LDL cholesterol and triglycerides exhibit highly significant variability; the greatest impact is seen with the triglycerides. Fasting time represents an independent factor for reduced LDL cholesterol and elevated triglyceride concentrations. There is a close association between elevated lipids and hepatic steatosis.
Lipids; Total cholesterol; LDL cholesterol; HDL cholesterol; Triglycerides; Fasting time; Population-based; Cross-sectional; Non-alcoholic fatty liver disease (NAFLD)
Elevated plasma preprovasopressin (copeptin) levels are associated with cardiovascular complications as well as with an increased risk for type 2 diabetes (T2D). Here, we studied, whether plasma copeptin is related to carotid intima-media thickness (IMT), a measure of early atherosclerosis, and may thus be one explanation for the high cardiovascular risk in T2D.
Plasma concentrations of copeptin and IMT of the common carotid artery were determined in 1275 participants of the population-based KORA F4 study. We used linear regression models to investigate associations between copeptin levels and IMT.
In the whole study group, copeptin levels were not significantly associated with IMT after adjustment for age and sex. Copeptin and IMT were significantly inversely associated after multivariable adjustment in the total cohort (β = -0.020 mm, 95% CI: -0.037 mm; -0.003 mm), in men (β = -0.035 mm, 95% CI: -0.061 mm; -0.009 mm) and in study participants with prediabetes (β = -0.041 mm, 95% CI: -0.078 mm; -0.005 mm) comparing quartile 4 vs quartile 1. The negative association of copeptin and IMT in men was present after adjustment for age alone. In women and patients with T2D, copeptin was not significantly associated with IMT.
Plasma copeptin was not associated with an increased IMT in our study cohort. In contrast, copeptin levels were related to a lower IMT in men and subjects with prediabetes, suggesting that elevated copeptin concentrations do not exert proatherogenic effects on carotid arteries.
Intima-media thickness; IMT; Atherosclerosis; Copeptin; AVP; Vasopressin; Diabetes
CYP2C19*2 polymorphism is related to metabolizer phenotypes resulting in reduced effectiveness in converting the antiplatelet drug clopidogrel to active drug. An association of the genotype itself with adverse outcomes is discussed. We investigated the prognostic value of carriage of the CYP2C19*2 allele in a high risk group of patients with prevalent coronary heart disease (CHD) at baseline during long-term follow-up under conditions of routine clinical care.
In n=1050 patients with stable CHD at baseline genotyping of CYP2C19 allele *2 (rs4244285; 681G>A) was performed. The Cox-proportional hazards model was employed to investigate the association of CYPC19*2 allele status with cardiovascular disease (CVD) events during eight year follow-up. The analysis was also performed in patients who did not take clopidogrel or ticlopidin.
Only the very few patients homozygous for a loss-of-function variant of CYP2C19, allele *2 (2.6%), had a statistically significantly higher incidence rate for secondary CVD events during long-term follow-up than wild-type carriers (50.8 versus 21.5 per 1000 patients years; rate for heterozygous carries 17.2 per 1000 patient years). The hazard ratio after adjustment for covariates compared to the wild-type carriers was 2.59 (95% confidence interval (CI) 1.27-5.28) and 0.80 (95% CI 0.52-1.23) for homozygous and heterozygous allele carriers, respectively.
In this medium-size group of patients with stable CHD homozygous carriers of the loss-of-function allele CYP2C19*2 were at increased risk for subsequent CVD events during 8 year follow-up independent of other risk factors. As only few patients carried the homozygous loss-of-function variant and we found overall no evidence for improved clinical utility, a benefit of genotyping in this patient population seems unlikely.
The hypothesis was tested that the systemic immune milieu in recent-onset type 1 diabetes is associated with residual beta cell function and other metabolic patient characteristics.
Methods and Findings
All patients (n = 89, 40% female) of the Diabetes and Atorvastatin (DIATOR) Trial were analyzed at recruitment, i.e. prior to receiving the study medication. Inclusion criteria were insulin dependent diabetes for 2 weeks to 3 months, age range 18–39 years, and islet cell autoantibodies. Blood samples were analyzed for 14 immune mediators by standard methods. Concentrations of all mediators correlated with at least one other mediator (p<0.05, Spearman correlation) giving rise to a network. Interleukin 1 receptor antagonist (IL1-RA) held a central position and was associated with both pro- and anti-inflammatory mediators. Further central elements were the pro-inflammatory mediators CRP and IL-6, the soluble adhesion molecules sICAM-1 and E-selectin, and MCP-4 which held a central position in the chemokine network. The two Th1-associated mediators IFNγ and IP-10 remained outside the network but correlated with each other. All correlations were positive (r = 0.25–0.72), i.e., high levels of pro-inflammatory mediators were accompanied by increased levels of anti-inflammatory mediators. IL-1RA was the only mediator associated with fasting and liquid mixed meal stimulated C-peptide concentrations (r = 0.31 and 0.24, p = 0.003 and 0.025, after adjustment for age, sex, BMI). There were associations between the immune mediator network and BMI (IL-1RA, CRP, IL-6, MCP-4, MIP-1ß) but few or no associations with HbA1c, insulin dose, lipid parameters, age or sex.
In patients with recent onset type 1 diabetes, systemic acute phase proteins, cytokines, chemokines and soluble adhesion molecules form a network. Among the few central elements IL-1RA has a dominant role. IL-1RA is associated with all other groups of mediators and is the only mediator which correlates (positively) with residual beta cell function.
ClinicalTrials.gov registration number: NCT00974740
The goal of this study was to determine the ability of a single, resting high-sensitivity troponin T (hsTnT) measurement to predict abnormal myocardial perfusion imaging (MPI) in patients presenting with acute chest pain to the emergency department (ED).
HsTnT assays precisely detect very low levels of troponin T, which may be a surrogate for the presence and extent of myocardial ischemia.
We included all patients from the ROMICAT I (Rule Out Myocardial Infarction Using Computer Assisted Tomography) trial, an observational cohort study, who underwent both single-photon emission computed tomography (SPECT)-MPI stress testing and 64-slice computed tomography angiography (CTA) and in whom hsTnT measurements were available. We assessed the discriminatory value of hsTnT for abnormal SPECT-MPI and the association of reversible myocardial ischemia by SPECT-MPI and the extent of coronary atherosclerosis by CTA to hsTnT levels.
Of the 138 patients (mean age 54 ± 11 years, 46% male), 19 (13.7%) had abnormal SPECT-MPI. Median hsTnT levels were significantly different between patients with normal and abnormal SPECT-MPI (9.41 pg/ml [interquartile range (IQR): 5.73 to 19.20 pg/ml] vs. 4.89 pg/ml [IQR: 2.34 to 7.68 pg/ml], p = 0.001). Sensitivity of 80% and 90% to detect abnormal SPECT-MPI was reached at hsTnT levels as low as 5.73 and 4.26 pg/ml, respectively. Corresponding specificity was 62% and 46%, and negative predictive value was 96% and 96%, respectively. HsTnT levels had good discriminatory ability for prediction of abnormal SPECT-MPI (area under the curve: 0.739, 95% confidence interval: 0.609 to 0.868). Both reversible myocardial ischemia and the extent of coronary atherosclerosis (combined model r2 = 0.19 with partial of r2 = 0.12 and r2 = 0.05, respectively) independently and incrementally predicted the measured hsTnT levels.
In patients with acute chest pain, myocardial perfusion abnormalities and coronary artery disease are predicted by resting hsTnT levels. Prospective evaluations are warranted to confirm whether resting hsTnT could serve as a powerful triage tool in chest pain patients in the ED before diagnostic testing and improve the effectiveness of patient management.
coronary computed tomographic angiography; high-sensitivity troponin T; myocardial perfusion imaging; single-photon emission computed tomography
Serum urate, the final breakdown product of purine metabolism, is causally involved in the pathogenesis of gout, and implicated in cardiovascular disease and type 2 diabetes. Serum urate levels highly differ between men and women; however the underlying biological processes in its regulation are still not completely understood and are assumed to result from a complex interplay between genetic, environmental and lifestyle factors. In order to describe the metabolic vicinity of serum urate, we analyzed 355 metabolites in 1,764 individuals of the population-based KORA F4 study and constructed a metabolite network around serum urate using Gaussian Graphical Modeling in a hypothesis-free approach. We subsequently investigated the effect of sex and urate lowering medication on all 38 metabolites assigned to the network. Within the resulting network three main clusters could be detected around urate, including the well-known pathway of purine metabolism, as well as several dipeptides, a group of essential amino acids, and a group of steroids. Of the 38 assigned metabolites, 25 showed strong differences between sexes. Association with uricostatic medication intake was not only confined to purine metabolism but seen for seven metabolites within the network. Our findings highlight pathways that are important in the regulation of serum urate and suggest that dipeptides, amino acids, and steroid hormones are playing a role in its regulation. The findings might have an impact on the development of specific targets in the treatment and prevention of hyperuricemia.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-013-0565-2) contains supplementary material, which is available to authorized users.
Gaussian Graphical Modeling; Metabolite network; Pathway reconstruction; Allopurinol; Uric acid; Purine metabolism
Cocaine users represent an Emergency Department (ED) population that has been shown to be at increased risk for ACS; however, there is controversy about whether this higher risk is mediated through advanced atherosclerosis. Thus, we aimed to determine whether history of cocaine use is associated with acute coronary syndrome (ACS) and coronary artery disease using coronary computed tomography (CT). In this matched cohort study, we selected patients with a history of cocaine use and age- and gender-matched controls from a large cohort of consecutive patients who presented with acute chest pain to the ED. Coronary atherosclerotic plaque as detected by 64-slice coronary CT was compared between the groups. Among 412 patients, 44 had a history of cocaine use (9%) and were matched to 132 controls (mean age: 46±6 years, 86% male). History of cocaine use was associated with a 6-fold higher risk for ACS (odds ratio: 5.79, 95%-confidence interval: 1.24–27.02, p=0.02), but was not associated with a higher prevalence of any plaque, calcified plaque, or non-calcified plaque (p=1.0, p=1.0; and p=0.58, respectively) or the presence of significant stenosis (p=0.09). History of cocaine use was also not associated with the extent of any, calcified, or non-calcified plaque (p=0.67, p=0.30, and p=0.12, respectively). These associations persisted after adjustment for other cardiovascular risk factors. In conclusion, among ED patients presenting with acute chest pain, history of cocaine use is associated with an increase in risk for ACS; however, this was not attributable to a higher presence or extent of coronary atherosclerotic plaque.
Compared to troponin alone, a dual-marker strategy with natriuretic peptides may improve acute coronary syndrome (ACS) diagnosis with a single blood draw and provide physiologic information regarding underlying heart disease. We evaluate the value of adding natriuretic peptides (myocyte stress markers) to troponins (myocardial injury markers) for diagnosing ACS in emergency department (ED) patients with chest pain.
In 328 patients (53 ± 12 years, 63% men) with an initially negative conventional troponin and nonischemic electrocardiogram who underwent 64-slice cardiac computed tomography (CT), we measured conventional troponin-T (cTnT), high-sensitivity troponin-T (hsTnT), N-terminal pro-B type natriuretic peptide (NT-proBNP), and mid-regional pro-atrial natriuretic peptide (MR-proANP). ACS was defined as myocardial infarction or unstable angina. CT was evaluated for coronary plaque, stenosis, and regional wall motion abnormality (RWMA).
Patients with ACS (n=29, 9%) had higher concentrations of each biomarker compared to those without (all p <0.01). Adding natriuretic peptides, especially NT-proBNP, to both cTnT orhsTnT improved the C-statistics and net reclassification index for ACS, largely driven by correctly reclassifying events. Dual-negative marker results improved sensitivity (cTnT 38% to 83–86%, hsTnT 59% to 86–90%; all p <0.01) and negative predictive value (cTnT94% to 97–98%, hsTnT 96% to 97–98%) for ACS. Patients with dual-negative markers had the lowest percentage of CT coronary plaque, stenosis, and RWMA (all p-trend <0.001).
Among ED patients with low-intermediate likelihood of ACS, combining natriuretic peptides with either conventional or highly-sensitive troponin improved discriminatory capacity and allowed for better reclassification of ACS, findings supported by structural and functional CT results.
natriuretic peptides; troponins; acute coronary syndrome; emergency department; computed tomography
AIM: To determine the prevalence of celiac disease in a randomly selected population sample.
METHODS: A total of 2157 subjects (1036 males; 1121 females) participating in a population-based cross-sectional study underwent laboratory testing for tissue transglutaminase and antibodies to immunoglobulin A, endomysium and antigliadin. In a second step, all subjects who had been examined serologically were surveyed using a questionnaire that included questions specific to celiac disease. Subjects with positive antibody titers and those with histories positive for celiac disease then underwent biopsy. At the first follow up, antibody titers were again determined in these subjects and subjects were questioned regarding symptoms specific for celiac disease and disorders associated with celiac disease. The second follow up consisted of a telephone interview with subjects positive for celiac disease.
RESULTS: Antibody tests consistent with celiac disease were reported in eight subjects, corresponding to an overall prevalence of 1:270 (8/2157). The prevalence among women was 1:224 and 1:518 in men. Classical symptoms were observed in 62.5% of subjects. Atypical celiac disease was present in 25.0%, and transient celiac disease in 12.5%. False-negative test results were returned in three subjects. This yields a sensitivity and specificity of 62.5% and 50.0%, respectively, for tissue transglutaminase immunoglobulin-A antibody; of 62.5% and 71.4% respectively, for endomysium antibody; and of 62.5% and 71.4%, respectively, for antigliadin antibody.
CONCLUSION: The prevalence rate in our collective lies within the middle tertile of comparable studies in Europe. The use of a single antibody test for screening purposes must be called into question.
Cross-sectional study; Celiac disease; Screening; Prevalence; Serology
Although epidemiologic data link biomarkers of cardiovascular risk with incident and prevalent coronary artery disease, exact anatomic relationships between biomarkers and coronary atherosclerosis as measured by coronary CT angiography remain unclear. Patients with acute chest pain who ultimately had no evidence of acute coronary syndrome underwent contrast-enhanced 64-slice coronary CT angiography to determine presence, extent and composition of coronary atherosclerotic plaque. We determined the differences in levels of blood biomarkers measured at the time of the CT scan between different CT-based atherosclerotic plaque groups. Among 313 patients (mean age: 51.6 ± 11 years, 62% male) high-sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-2 were associated with the extent of calcified plaque (P = 0.03 and P<0.001), while hs-CRP and apolipoprotein A1 were associated with the extent of non-calcified plaque (P = 0.03 and P = 0.004; respectively). Despite a generally lower risk profile, subjects with exclusively non-calcified plaque had significantly higher levels of hs-CRP and oxidized low-density lipoprotein (P = 0.01 and P = 0.03; respectively) and lower levels of adiponectin (P = 0.03) when compared to subjects with calcified plaque (n = 130, 42%). Biomarkers reflecting inflammation, vascular remodeling, oxidation, and lipoprotein metabolism maybe associated with different patterns of coronary atherosclerosis as quantified by coronary CT angiography.
Biomarkers; Atherosclerosis; Cardiac CT; Imaging; Coronary artery disease
Elevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.
Methodology/ Principal Findings
Data of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of −0.37 ng/ml (p = 1.87×10−103) in KORA and −0.35 ng/ml (p = 5.11×10−84) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.
Our findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.
The association between blood glucose and carotid intima-media thickness (CIMT) is considered to be established knowledge. We aimed to assess whether associations between different measures of glycaemia and CIMT are actually independent of anthropometric variables and metabolic risk factors. Moreover, we checked published studies for the adjustment for shared risk factors of blood glucose and CIMT.
Fasting glucose, 2-hour glucose, HbA1c, and CIMT were measured in 31-81-years-old participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Southern Germany (n = 2,663). CIMT was assessed according to the Rotterdam protocol. Linear and logistic regression models with adjustment for age, sex, anthropometric measures, hypertension, and dyslipidaemia were fitted to assess the association between continuous measures of glycaemia, and categories of glucose regulation, respectively, with CIMT.
We found a 0.10 mm increase (95%-confidence interval: 0.08–0.12) in CIMT in subjects with compared to subjects without diabetes in crude analysis. This increase was not significant in age-sex adjusted models (p = 0.17). Likewise, neither impaired fasting glucose (p = 0.22) nor impaired glucose tolerance (p = 0.93) were associated with CIMT after adjustment for age, sex, and waist circumference. In multivariable adjusted models, age, sex, hypertension, waist circumference, HDL and LDL cholesterol, but neither fasting glucose nor 2-hour glucose nor HbA1c were associated with elevated CIMT. Literature findings are inconclusive regarding an independent association of glucose levels and CIMT.
CIMT is highly dependent on traditional cardiovascular risk factors, but no relationships between blood glucose and CIMT were found after adjustment for age, sex, and anthropometric variables.
To assess the association between serum 25-hydroxyvitamin D (25-OHD) and incident type 2 diabetes and to determine whether the association is mediated by subclinical inflammation.
RESEARCH DESIGN AND METHODS
Using a case-cohort design, baseline levels of 25-OHD were measured in 416 case subjects with incident type 2 diabetes and 1,267 noncase subjects selected from a source population of 7,936 middle-aged participants in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) study.
A significant inverse association was observed between serum 25-OHD and incident type 2 diabetes after adjustment for diabetes risk factors and season. The hazard ratio (HR) and 95% CI comparing tertile extremes was 0.63 (0.44–0.90) (Ptrend = 0.010). Further adjustment for C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, and interferon-γ–inducible protein-10 attenuated this association by 16% (HR 0.73 [0.50–1.05], P = 0.090).
Vitamin D status is inversely related to type 2 diabetes risk and our data suggest that this association may be partially mediated by subclinical inflammation.
So far it is unclear whether the association between serum uric acid (SUA), inflammatory cytokines and risk of atherosclerosis is causal or an epiphenomenon. The aim of the project is to investigate the independent prognostic relationship of inflammatory markers and SUA levels with adverse cardiovascular outcomes in a patient population with stable coronary heart disease (CHD).
SUA, C-reactive protein (CRP) and interleukin (IL)-6 were measured at baseline in a cohort of 1,056 patients aged 30–70 years with CHD. Cox proportional hazards model was used to determine the prognostic value of these markers on a combined CVD endpoint during eight year follow-up after adjustment for covariates.
For 1,056 patients with stable coronary heart disease aged 30–70 years (mean age 58.9 years, SD 8.0) follow-up information and serum measurements were complete and n = 151 patients (incidence 21.1 per 1000 patients years) experienced a fatal or non-fatal CVD event during follow-up (p-value = 0.05 for quartiles of SUA, p = 0.002 for quartiles of CRP, p = 0.13 for quartiles of IL-6 in Kaplan-Meier analysis). After adjustment for age, gender and hospital site the hazard ratio (HR) for SUA increased from 1.37 to 1.65 and 2.27 in the second, third, and top quartile, when compared to the bottom one (p for trend <0.0005). The HR for CRP increased from 0.85 to 0.98 and 1.64 in the respective quartiles (p for trend 0.02). After further adjustment for covariates SUA still showed a clear statistically significant relationship with the outcome (p for trend 0.045), whereas CRP did not (p for trend 0.10).
The data suggest that compared to inflammatory markers such as CRP and IL-6 serum uric acid levels may predict future CVD risk in patients with stable CHD with a risk increase even at levels considered normal.
More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design.
Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived.
Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events.
Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.
We examined the association between retinol-binding protein 4 (RBP4), a novel adipokine, and prediabetes (isolated impaired fasting glucose [i-IFG], isolated impaired glucose tolerance [i-IGT], and combined IFG and IGT) in men and women aged 32–81 years.
RESEARCH DESIGN AND METHODS
The analysis was based on 2,614 participants without previously diagnosed diabetes and those with newly diagnosed diabetes of the Cooperative Health Research in the Region of Augsburg (KORA) F4 Study, conducted from 2006 to 2008 in southern Germany. Plasma RBP4 was analyzed by immunonephelometry.
In logistic regression analysis, RBP4 levels in the fourth quartile versus the first quartile were significantly associated with prediabetes (i-IGT, i-IFG, and IFG/IGT; reference normal glucose tolerance) independent of known metabolic risk factors and lifestyle variables (odds ratio 1.63 [95% CI 1.17–2.27] after multivariable adjustment). Stratification by sex showed generally similar results.
RBP4 levels were associated with prediabetes in individuals from the general population. Prospective studies investigating the impact of RBP4 on the development of glucose intolerance are needed.
Chronic kidney disease (CKD) represents a global public health problem. Few data exist in the elderly. The objective of the current study is to estimate the prevalence of CKD by means of various established and new equations and to identify the main determinants of CKD in elderly.
The ActiFE Ulm (Activity and Function in the Elderly in Ulm) study is a population-based cohort study in people of 65 years and older. Kidney function was assessed by means of estimated glomerular filtration rate (eGFR) based on two creatinine- (Cr-; MDRD, CKD-EPI) and one cystatin C - (CysC-) based method. The relationship between various potential risk factors and CKD was quantified using unconditional logistic regression.
A total of 1471 subjects were in the final analysis (mean age 75.6 years, SD 6.56). Overall, prevalence of CKD (eGFR < 60 mL/min/1.73 m2) was 34.3% by MDRD, 33.0% by CKD-EPI, and 14.6% by the CysC-based eGFR. All eGFRs showed statistically significant correlations with C-reactive protein, uric acid, as well as with lipid values. In multivariable analysis age was clearly related to prevalence of CKD and the risks were highest with the CysC-based equation. Females had a higher risk for CKD stages 3–5 with MDRD (OR 1.63; 95% CI: 1.23–2.16) whereas the OR was 1.23 (95% CI 0.92–1.65) with the CKD-Epi and OR = 0.89 (95% CI 0.58–1.34) with the CysC-based equation after multivariable adjustment. Although the cystatin C based definition of CKD resulted in a lower prevalence compared to the creatinine based ones, other measures of renal damage such as albuminuria were more prevalent in those defined by CysC-eGFR.
Prevalence of CKD is very variable based on the used estimating equation. More work is needed to evaluate the various estimating equations especially in elderly before we are able to assess the practical consequences of the observed differences.
Elderly; Chronic kidney disease; Population-based study; Estimating equations; Risk factors
Plasma levels of high density lipoprotein cholesterol (HDL-C) are known to be heritable, but only a fraction of the heritability is explained. We used a high density genotyping array containing SNPs from HDL-C candidate genes selected on known biology of HDL-C metabolism, mouse genetic studies, and human genetic association studies. SNP selection was based on tagging-SNPs but also included low-frequency nonsynonymous SNPs.
Methods and Results
Association analysis in a cohort containing extremes of HDL-C (case-control, n=1733) provided a discovery phase, with replication in three additional populations for a total meta-analysis in 7,857 individuals. We replicated the majority of loci identified through genome wide association studies and present on the array (including ABCA1, APOA1/C3/A4/A5, APOB, APOE/C1/C2, CETP, CTCF-PRMT8, FADS1/2/3, GALNT2, LCAT, LILRA3, LIPC, LIPG, LPL, LRP4, SCARB1, TRIB1, ZNF664), and provide evidence suggestive of association in several previously unreported candidate gene loci (including ABCG1, GPR109A/B/81, NFKB1, PON1/2/3/4). There was evidence for multiple, independent association signals in five loci, including association with low frequency nonsynonymous variants.
Genetic loci associated with HDL-C are likely to harbor multiple, independent causative variants, frequently with opposite effects on the HDL-C phenotype. Cohorts composed of extreme individuals may be efficiently used in a case-control discovery of quantitative traits.
lipids; genetic association; HDL cholesterol; cardiovascular diseases
A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin.
The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r2 = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin.
Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators.
The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events.
Methods and Findings
We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75–1.42] and 1.11 [0.81–1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years).
High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.
Serum type II secretory phospholipase A2 (sPLA2-IIa) has been found to be predictive of adverse outcomes in patients with stable coronary heart disease. Compounds targeting sPLA2-IIa are already under development. This study investigated if an association of sPLA2-IIa with secondary cardiovascular disease (CVD) events may be of causal nature or mainly a matter of confounding by correlated cardiovascular risk markers.
Eight-year follow-up data of a prospective cohort study (KAROLA) of patients who underwent in-patient rehabilitation after an acute cardiovascular event were analysed. Associations of polymorphisms (SNP) in the sPLA2-IIa-coding gene PLA2G2A with serum sPLA2-IIa and secondary fatal or non-fatal CVD events were examined by multiple regression. Hazard ratios (HR) were compared with those expected if the association between sPLA2-IIa and CVD were causal. The strongest determinants of sPLA2-IIa (rs4744 and rs10732279) were associated with an increase of serum concentrations by 81% and 73% per variant allele. HRs (95% confidence intervals) estimating the associations of the SNPs with secondary CVD events were increased, but not statistically significant (1.16 [0.89–1.51] and 1.18 [0.91–1.52] per variant allele, respectively). However, these estimates were very similar to those expected when assuming causality (1.18 and 1.17), based on an association of natural log-transformed sPLA2-IIa concentration with secondary events with HR = 1.33 per unit.
The present findings regarding genetic polymorphisms, determination of serum sPLA2-IIa, and prognosis in CVD patients are consistent with a genuine causal relationship and thus might point to a valid drug target for prevention of secondary CVD events.
Background: Increasing evidence suggests a proatherogenic role for lipoprotein-associated phospholipase A2 (Lp-PLA2). A meta-analysis of published cohorts has shown that Lp-PLA2 is an independent predictor of coronary heart disease events and stroke.
Objective: In this study, we investigated whether the association between air pollution and cardiovascular disease might be partly explained by increased Lp-PLA2 mass in response to exposure.
Methods: A prospective longitudinal study of 200 patients who had had a myocardial infarction was performed in Augsburg, Germany. Up to six repeated clinical examinations were scheduled every 4–6 weeks between May 2003 and March 2004. Supplementary to the multicenter AIRGENE protocol, we assessed repeated plasma Lp-PLA2 concentrations. Air pollution data from a fixed monitoring site representing urban background concentrations were collected. We measured hourly means of particle mass [particulate matter (PM) < 10 µm (PM10) and PM < 2.5 µm (PM2.5) in aerodynamic diameter] and particle number concentrations (PNCs), as well as the gaseous air pollutants carbon monoxide (CO), sulfur dioxide (SO2), ozone (O3), nitric oxide (NO), and nitrogen dioxide (NO2). Data were analyzed using mixed models with random patient effects.
Results: Lp-PLA2 showed a positive association with PM10, PM2.5, and PNCs, as well as with CO, NO2, NO, and SO2 4–5 days before blood withdrawal (lag 4–5). A positive association with O3 was much more immediate (lag 0). However, inverse associations with some pollutants were evident at shorter time lags.
Conclusion: These preliminary findings should be replicated in other study populations because they suggest that the accumulation of acute and subacute effects or the chronic exposure to ambient particulate and gaseous air pollution may result in the promotion of atherosclerosis, mediated, at least in part, by increased levels of Lp-PLA2.
air pollution; atherosclerosis; epidemiology; inflammation; lipoprotein-associated phospholipase A2; myocardial infarction; panel study
This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population-based MONICA/KORA Augsburg cohort.
Methods and Findings
Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC), changes in Akaike's information criterion (ΔAIC), integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF-β1, sE-selectin, sICAM-1; all measured in nonfasting serum) increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes) increased the AUC to 0.803 (ΔAUC [95% CI] 0.111 [0.092–0.149] and 0.113 [0.093–0.149], respectively, compared to the basic model). The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (ΔAUC [95% CI] 0.044 [0.028–0.066] compared to the cardiometabolic risk model). Corresponding AUCs for incident coronary events were 0.807, 0.825 (ΔAUC [95% CI] 0.018 [0.013–0.038] compared to the basic model), 0.845 (ΔAUC [95% CI] 0.038 [0.028–0.059] compared to the basic model) and 0.851 (ΔAUC [95% CI] 0.006 [0.003–0.021] compared to the cardiometabolic risk model), respectively.
Inclusion of multiple inflammation-related biomarkers into a basic model and into a model including cardiometabolic risk factors significantly improved the prediction of type 2 diabetes and coronary events, although the improvement was less pronounced for the latter endpoint.
P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 × 10−61) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 × 10−23). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 × 10−41 and rs649129, P = 1.22 × 10−15, respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.