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Background and Aims: Various pro- and anti-inflammatory biomarkers are involved in the process of atherosclerosis. We analyzed the association of different biomarkers with coronary plaque volume and vulnerable plaque subcomponents., Methods: In 301 patients undergoing coronary CT angiography (CTA), total coronary plaque volume (TPV) and subcomponents including non-calcified plaque volume (NCPV) and vulnerable plaque burden were quantified using semi-automated software. Serum was analyzed for various cytokines., Results: Out of 301 patients, 207 (69%) were male. The mean age was 59 ± 10 years. Patients were divided using the median of TPV, NCPV and vulnerable plaque burden. In univariable analysis, patients with high TPV, high NCPV and high vulnerable plaque burden showed significant higher serum levels for IFNƔ, IL-1a, -2, -4, -10 and -17 and significant lower levels for IL-8 and MCP-1 (all p < 0.05). Multivariable analysis showed positive associations between high vulnerable plaque burden, IL-1a (OR 2.60, p = 0.001) and Eotaxin (OR 1.89, p = 0.020), and inverse association to MCP-1 (OR 0.33, p < 0.001), independent of age, gender and CVRF. In exploratory subanalyses, patients with presence of atherosclerosis (n = 247; 82%) showed significantly higher levels of IL-17 in all subgroups with high vulnerable plaque burden, irrespective of overall plaque volume (all p < 0.001)., Conclusions: The cytokine profile significantly differs between patients with high and low coronary plaque volume. IL-1a and IL-17 seem to play a major proatherogenic role in vulnerable plaque formation, whereas MCP-1 paradoxically portends protective effects. Longitudinal studies with serial cytokine testing are needed to identify potential targets for therapeutic interventions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Increased attenuation of pericoronary adipose tissue (PCAT) around the right coronary artery (RCA) derived from coronary CTA might detect coronary inflammation. We investigated a potential association between RCA PCAT attenuation and serum levels of atherosclerosis-relevant cytokines and MACE (coronary revascularization, myocardial infarction and/or cardiac death)., Methods: Blood samples of 293 clinically stable individuals (59.0 ​± ​9.8 years, 69% males) were analyzed for atherosclerosis-relevant cytokines including interleukin (IL)-2, IL- 4, IL-6, IL-7, IL-8, IL-10, IL-13, IL-15, IL-17, TNF-a, IP-10, CRP, MCP-1, MIP-1a, Eotaxin and GM-CSF. Subjects also underwent coronary calcium scoring (CCS) followed by CTA. PCAT CT attenuation was measured around the RCA using semi-automated software. Increased RCA PCAT attenuation was defined as PCAT attenuation above the 75th percentile (>-73.5 HU). To assess MACE, 232 individuals were followed for a mean duration of 9.6 ​± ​2.1 years., Results: In patients with increased RCA PCAT attenuation the serum levels of MCP-1 were increased (p ​< ​0.01), whereas levels of anti-inflammatory mediators IL-4 and -13 were significantly reduced (each p ​< ​0.05). Adipocytokine MCP-1 (r ​= ​0.23, p ​< ​0.01) and pro-inflammatory mediator IL-7 (r ​= ​0.12, p ​= ​0.04) showed a mild positive correlation with RCA PCAT attenuation, whereas anti-inflammatory mediators Il-4, -10 and -13 correlated inversely (each r < -0.12, each p ​< ​0.05). 40/232 patients experienced MACE during follow-up. In multivariable Cox regression analysis increased RCA PCAT attenuation was shown to be an independent predictor of MACE (HR 2.01, p ​= ​0.044)., Conclusions: Increased RCA PCAT CT attenuation shows a weak association with serum levels of selected atherosclerosis-relevant inflammatory biomarkers. Increased RCA PCAT attenuation is an independent predictor of MACE and may potentially guide future prevention strategies in stable patients., Competing Interests: Declaration of competing interest None., (Copyright © 2021 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor receptor 2 (VEGFR2) are associated with coronary artery disease, hypertension and myocardial infarction. However, their association with atherosclerosis remains to be fully elucidated. The purpose of the present study was to determine whether SNPs are involved in atherogenesis, by analyzing their impact on human umbilical vein endothelial cells (HUVECs) under laminar and non‑uniform shear stress in a well‑established in vitro model that simulates shear stress‑induced proatherogenic processes at vessel bifurcations. All experiments were performed using freshly isolated HUVECs. Three SNPs in the VEGFR2 gene (rs1870377 T>A, rs2071559 A>G and rs2305948 C>T) were genotyped and the expression levels of VEGFR2 were semi‑quantitatively determined using western blotting. Subsequently, the HUVECs were seeded in bifurcating flow‑through cell culture slides and flow (9.6 ml/min) was applied for 19 h, including tumor necrosis factor‑α stimulation during the final 2 h of flow. The protein expression levels of VCAM‑1, E‑selectin and VEGFR2 and the adhesion of THP‑1 cells were analyzed in laminar and non‑uniform shear stress regions. Data were analyzed for associations with the respective SNPs. The total expression of VEGFR2 was significantly lower under non‑uniform shear stress than under laminar shear stress conditions, independent of the genotype. The expression of VEGFR2 between the different shear stress patterns was not significantly altered by the different SNPs. The expression levels of VCAM‑1 and E‑selectin were lower in the A/A genotype compared with those in other genotypes in rs1870377 T>A and rs2071559 A>G. In conclusion, the results suggested that SNPs within the VEGFR2 gene have a significant impact on shear stress‑related endothelial activation.

A type 1 immune response is involved in atherosclerosis progression, whereas the role of a type 2 polarization, especially with regard to an enhanced T helper (T h )2 cell differentiation, is still unclear. Helminths trigger type 2 immune responses, protecting the host from inflammatory disorders. We investigated whether an increased type 2 polarization by administration of Litomosoides sigmodontis adult worm extract (LsAg) affects atherosclerosis in apolipoprotein E-deficient (ApoE -/- ) mice. Injections of 50 µg LsAg, i.p. into ApoE -/- mice induced a type 2 immune response shown by increased frequencies of peritoneal eosinophils and alternatively activated macrophages. To analyze the effect of LsAg on atherosclerosis initiation, ApoE -/- mice received a high-fat diet for 12 wk and weekly injections of 50 µg LsAg from wk 5 to 12. Therapeutic effects on advanced atherosclerosis were analyzed in mice that were fed a high-fat diet for 12 wk followed by 12 wk of normal chow and weekly LsAg injections. Both preventive and therapeutic LsAg application significantly decreased plaque size. Therapeutic treatment even caused regression of plaque size and macrophage density in the aortic root and reduced T h 1-specific gene expression and intraplaque inflammation. In addition, plaque size after therapeutic treatment was inversely correlated with plaque-infiltrated alternatively activated macrophages. In vitro , LsAg treatment of HUVECs reduced intracellular levels of phosphorylated NF-κB-p65, IκB-α, and JNK1/2. In bifurcation flow-through slides, THP-1 cell adhesion to a HUVEC monolayer was decreased by LsAg in regions of nonuniform shear stress. Applying inhibitors of the respective kinases suggests JNK1/2 inhibition is involved in the suppressed cell adhesion. A switch to an enhanced type 2 immune response by LsAg exerts antiatherogenic effects on murine plaque development, indicating a protective role of a hampered type 1 polarization. In vitro , LsAg affects endothelial signaling pathways, among which JNK1/2 inhibition seems to be involved in the suppression of monocytic cell adhesion under proatherogenic shear stress.-Constanze, K., Tauchi, M., Furtmair, R., Urschel, K., Raaz-Schrauder, D., Neumann, A.-L., Frohberger, S. J., Hoerauf, A., Regus, S., Lang, W., Sagban, T. A., Stumpfe, F. M., Achenbach, S., Hübner, M. P., Dietel, B. Filarial extract of Litomosoides sigmodontis induces a type 2 immune response and attenuates plaque development in hyperlipidemic ApoE-knockout mice.

Aims: Device sizing for LAA closure using transoesophageal echocardiography (TEE) can be challenging due to complex LAA anatomy. We investigated whether the use of 3D-printed left atrial appendage (LAA) models based on preprocedural computed tomography (CT) permits accurate device sizing., Methods and Results: Twenty-two (22) patients (73±8 years, 55% male) with atrial fibrillation requiring anticoagulation at high bleeding risk underwent LAA closure (WATCHMAN device). Preprocedurally, LAA was sized by TEE and third-generation dual-source CT. Based on CT, 3D printing models of LAA anatomy were created for simulation of device implantation. Device compression was assessed in a CT scan of the 3D model with the implanted device. Implantation was successful in all patients. Mean LAA ostium diameter based on TEE was 22±4 mm and based on CT 25±3 mm (p=0.014). Predicted device size based on simulated implantation in the 3D model was equal to the device finally implanted in 21/22 patients (95%). TEE would have undersized the device in 10/22 patients (45%). Device compression determined in the 3D-CT model corresponded closely with compression upon implantation (16±3% vs. 18±5%, r=0.622, p=0.003)., Conclusions: Patient-specific CT-based 3D printing models may assist device selection and prediction of device compression in the context of interventional LAA closure.

Osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) are regulators of bone remodeling, but are also considered to play important roles in coronary artery disease (CAD). This study evaluated potential associations of soluble (s) RANKL and OPG with atherosclerosis-relevant cytokines. Blood was collected from 414 individuals who presented to our hospital with intermediate likelihood for CAD for further examination. Plasma concentrations of total sRANKL, OPG, and 20 cytokines were measured using sandwich-type enzyme-linked immunoassays (ELISAs; OPG and sRANKL) and Luminex laser-based fluorescence analysis and correlated with each other. The plasma levels of interferon-γ (IFN-γ) and the T-helper cell 2 cytokines interleukin-4 (IL-4) and IL-13 showed a positive correlation with sRANKL. The association with sRANKL levels was negative for IFN-γ-induced protein-10 (IP-10) and monocyte chemotactic protein-1 (MCP-1). The strongest independent association with sRANKL in multivariable analyses was found for IFN-γ (positive) and IP-10 (negative), while IL-13 showed a positive and independent association with OPG plasma levels. OPG and sRANKL plasma levels correlate strongly and independently with specific circulating atherosclerosis-related cytokines in patients with intermediate cardiovascular risk.

Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease., (© 2017 Uderhardt et al.)

Background: Increased epicardial fat volume (EFV) has been shown to be associated with coronary atherosclerosis. While it is postulated to be an independent risk factor, a possible mechanism is local or systemic inflammation. We analyzed the relationship between coronary atherosclerosis, quantified by coronary calcium in CT, epicardial fat volume and systemic inflammation., Methods: Using non-enhanced dual-source CT, we quantified epicardial fat volume (EFV) and coronary artery calcium (CAC) in 391 patients who underwent coronary computed tomography for suspected coronary artery disease. In addition to traditional risk factors, serum markers of systemic inflammation were measured (IL-1α, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10,IL-12, IL-13, IL-15, IL-17, IFN-γ, TNF-α, hs-CRP, GM-CS, G-CSF, MCP-1, MIP-1, Eotaxin and IP-10). In 94 patients follow-up data were obtained after 1.9 ± 0.5 years., Results: The 391 patients had a mean age of 60 ± 10 years, and 69 % were males. Mean EFV was 116 ± 50 mL. Median CAC was 12 (IQR 0; 152). CAC and EFV showed a significant correlation (ρ = 0.37; P < 0.001). EFV and CAC were significantly correlated with the traditional risk factors like age, male gender, diabetes, smoking and hypertension. With regard to biomarkers, CAC was significantly associated (negatively) to G-CSF and IL-13. EFV (median binned) was significantly associated (positively) with IP-10 (P = 0.002) and MCP-1 (ρ = 0.037). In follow-up, EFV showed a mean annualized progression of 6 mL (IQR 3; 9) (P < 0.001); CAC progressed by a mean of six Agatston Units (IQR 0; 30). The progression of CAC was significantly correlated with the extent of EFV (P < 0.001) while there was no significant correlation between progression of EFV or CAC with systemic inflammation markers., Conclusion: Epicardial fat volume and the baseline extent as well as progression of coronary atherosclerosis-measured by the calcium score-are significantly correlated. While both baseline EFV and CAC displayed significant correlations with systemic inflammation markers, biomarkers were not predictive of the progression of CAC or EFV.

Introduction: The stimulatory effects of CRP (C-reactive protein) on endothelial cells are mainly mediated via FcγRIIa. This receptor exists in two different allotypes bearing either arginine (R131) or histidine (H131) at the extracellular amino acid position 131 of the mature protein, but only FcγRIIa-R131 displays high avidity for CRP. This study investigated the role of the FcγRIIa genotype in CRP-stimulated endothelial cells., Materials and Methods: We tested the effects of CRP on expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the endothelial release of pro-inflammatory molecules as a function of the FcγRIIa-genotype (FcγRIIa-H/H131, FcγRIIa-H/R131, FcγRIIa-R/R131) in HUVEC (Human Umbilical Vein Endothelial Cells). HUVEC were grouped according to their FcγRIIa status by genotyping with an allele specific nested-PCR. The expression of ICAM-1, VCAM-1, and E-selectin on HUVEC was detected by flow cytometry. The release of soluble markers (sCD40L, IL-6, IL-8, MCP-1, tPA, sP-selectin, and sVCAM-1) was measured using a multiplex assay for flow cytometry., Results and Conclusions: CRP-stimulated expression of ICAM-1 and E-selectin was dependent on the specific FcγRIIa-genotype, with most pronounced induction in HUVEC with the FcγRIIa-R/R genotype, followed by H/R and H/H. In accordance with this finding, the supernatants of stimulated HUVEC with the R/R genotype showed significantly higher levels of tPA, MCP-1, and IL-6. Our data show that CRP stimulates the expression of adhesion molecules and the release of soluble markers by HUVEC as a function of the FcγRIIa-genotype. These findings could be relevant in the context of risk stratification in patients with cardiovascular disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Hypertension is one of the most prominent risk factors for coronary artery disease (CAD). Treatment of hypertension is therefore important for reducing cardiovascular events and the progression of atherosclerosis. Several treatment strategies are common in clinical practice for example the use of ACE-blockers or angiotensin receptor II blockers (ARBs), so called sartans. Telmisartan, belonging to the class of ARBs, was shown to exert anti-inflammatory effects besides the blood pressure lowering., Methods: In this work, two separate substudy groups of hypertensives were compared. 16 patients with arterial hypertension have been treated with telmisartan (initial 40 mg Kinzalmono®) for 7.3 ± 4.4 months. The telmisartan group was compared to a matched control group including 31 hypertensive patients without telmisartan treatment with a follow up period of 1.9 ± 0.5 years. Serum samples from the beginning and the end of follow up were analyzed with Luminex® technology for 26 cytokines and chemokines. The baseline scores of coronary artery calcification (CAC) were gathered by multislice detector computer tomography., Results: After 7 months of telmisartan treatment and 2 years in control patients most of the measured analytes did not change significantly. MCP-1 (P=0.001; P<0.001) was increased significantly in both telmisartan and control group. The relative decrease in IP-10 and TNF-α levels was observed in telmisartan group, as opposed to the increase in control (telmisartan vs. control P=0.048; P=0.01). No linear rank-correlation between measured analytes and the initial CAC was found., Conclusion: Telmisartan reduced blood pressure in patients with atherosclerosis and arterial hypertension within a short time period, whereas the inflammatory status of these patients remained largely unchanged. An involvement of telmisartan in the regulation of inflammatory and anti-inflammatory mediators in the context of CAD and CAC is possible, but cannot clearly be assumed based on the present findings., (Copyright © 2013. Published by Elsevier Ltd.)

Patients with Systemic Lupus Erythematosus (SLE) carry an increased risk for the development of coronary artery disease (CAD). The R131 allele of the Fc gamma receptor IIa (FcγRIIa) is associated with SLE incidence and disease severity but also with CAD. Compared to stable angina pectoris (SAP) the unstable angina (UAP), as a manifestation of destabilizing CAD, is associated with increased risk of persistent instability, myocardial infarction, and death. Identification of clinically relevant determinants for unstable angina promises reduction of UAP-associated mortality in patients with SLE. We conducted a clinical study among 553 consecutive patients with stable angina pectoris (n = 330) and unstable angina pectoris (n = 223). All patients were genotyped for a frequent functional variant at position 131 of the mature FcγRIIa. UAP, but not SAP was significantly associated with the R/R131 genotype (P < 0.001). In troponin-negative patients with angina carrying the R/R131 genotype the odds ratio for suffering from UAP was 4.02 (95% confidence interval, 2.52-6.41) compared to those with non-R/R131 genotypes. In a multivariable analysis, the R/R131 genotype independently predicted the risk for development of UAP in a model adjusted for classical atherogenic risk factors. Our data imply that risk stratification of SLE- and other high risk patients with troponin-negative angina could be significantly improved by FcγRIIa genotyping.

Background and Purpose: Patients with acute cerebrovascular events are susceptible to serious cardiac arrhythmias, but data on the time course and the determinants of their onset are scarce., Methods: The prospective Stroke-Arrhythmia-Monitoring-Database (SAMBA) assessed cardiac arrhythmias with need for urgent evaluation and treatment in 501 acute neurovascular patients during the first 72 hours after admission to a monitored stroke unit. Arrhythmias were systematically detected by structured processing of telemetric data. Time of arrhythmia onset and predisposing factors were investigated., Results: Significant cardiac arrhythmias occurred in 25.1% of all patients. Incidence was highest during the first 24 hours after admission. Serious arrhythmic tachycardia (ventricular or supraventricular>130 beats/min) was more frequent than bradycardic arrhythmia (sinus-node dysfunction, bradyarrhythmia, or atrioventricular block °II and °III). Arrhythmias were independently associated with higher age and severer neurological deficits as measured by the National Institutes of Health Stroke Scale on admission., Conclusions: The risk for significant cardiac arrhythmia after an acute cerebrovascular event is highest during the first 24 hours of care and declines with time during the first 3 days. Along with established vascular risk factors, the National Institutes of Health Stroke Scale may be considered for a stratified allocation of monitoring capabilities., Clinical Trial Registration: URL: www.clinicaltrials.gov. Unique identifier: NCT01177748.

Background and Purpose: Anticoagulation is a highly effective secondary prevention in patients with cardioembolic stroke and atrial fibrillation/flutter (AF). However, the condition remains underdiagnosed, because paroxysmal AF may be missed by diagnostic tests in the acute phase. In this study, the sensitivity of AF detection was assessed for serial electrocardiographic recordings and continuous stroke unit telemetric monitoring with or without a structured algorithm to analyze telemetric data (SEA-AF)., Methods: Three hundred forty-six consecutive patients with acute ischemic stroke were prospectively included and subjected to standard telemetric monitoring. In addition, telemetric data were separately analyzed following SEA-AF, consisting of a structured evaluation of episodes with high risk for AF and a chronological beat-to-beat screening of the full registration. Serial electrocardiograms were conducted in 24-hour intervals., Results: Median effective telemetry monitoring time was 75.5 hours (interquartile range 64-86 hours). Overall, AF was diagnosed in 119 of 346 patients (34.4%). The structured reading algorithm was the most sensitive method to detected AF. Conventional telemetry and serial electrocardiographic assessments were less effective. However, only 35% of patients with previously documented paroxysmal AF and negative baseline electrocardiogram demonstrated AF episodes during monitoring., Conclusions: Continuous stroke unit telemetry using SEA-AF shows a significantly higher detection rate for AF compared with daily electrocardiographic assessments and standard telemetry without structured reading. The low overall probability to detect paroxysmal AF with either method during the first days after stroke demonstrates the urgent need for complementary diagnostic strategies such as long-term monitoring and frequent follow-up assessments. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT01177748.

Background: Coronary artery calcification (CAC) is a marker for the presence and extent of coronary atherosclerotic plaques and can be detected non-invasively by multi-detector row CT (MDCT). Well known predictors of CAC are age, gender, and the classical atherogenic risk factors. CAC is associated with atherosclerotic plaque burden, but it is still elusive if atherosclerosis-relevant cytokines and chemokines are also associated with CAC., Methods: We conducted a clinical study among 455 consecutive individuals who underwent coronary calcium assessment performed by MDCT. Before MDCT, blood was drawn and subsequently analyzed for 20 different atherosclerosis-relevant cytokines and chemokines using a Luminex-laser-based fluorescence analysis., Results: Using univariate analyses, CAC patients revealed significantly higher levels of the chemokines IP-10 (P=0.047) and eotaxin (P=0.031) as compared to non-CAC patients. In multivariate analyses using common thresholds for calcium burden, the three cytokines interleukin-6 (P=0.028), interleukin-8 (P=0.009), and interleukin-13 (P=0.024) were associated with high coronary calcium levels after adjustment for classical variables and risk factors., Conclusions: In a large group of individuals with atypical chest pain and a low to intermediate likelihood for coronary artery disease elevated plasma levels of IL-6 and reduced levels of IL-8 and IL-13 were predictive for distinct coronary artery calcification. These findings support a specific role of these cytokines in coronary calcification., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Aims: Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach., Methods and Results: We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPs showed association with MI at P<1 × 10(-3) in two-sided logistic regression. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silico analysis (P<0.05 for each GWA sample): five SNPs at 9p21.3, a well-known CAD/MI locus, two SNPs at 10p11.21, and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association (P=9.54 × 10(-4)), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P=1.27 × 10(-11) [odds ratio (OR) = 1.15 (1.11-1.20)]., Conclusion: Analysis of a GWA study followed by in silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases.

Background: Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD)., Methods and Results: A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5))., Conclusion: Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.