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Rationale: One measure of protein glycosylation (GlycA) has been reported to predict higher cardiovascular risk by reflecting inflammatory pathways., Objective: The main objective of this study is to assess the role of a comprehensive panel of IgG glycosylation traits on traditional risk factors for cardiovascular disease and on presence of subclinical atherosclerosis in addition to GlycA., Methods and Results: We measured 76 IgG glycosylation traits in 2970 women (age range, 40-79 years) from the TwinsUK cohort and correlated it to their estimated 10-year atherosclerotic cardiovascular disease risk score and their carotid and femoral plaque measured by ultrasound imaging. Eight IgG glycan traits are associated with the 10-year atherosclerotic cardiovascular disease risk score after adjusting for multiple tests and for individual risk factors-5 with increased risk and 3 with decreased risk. These glycans replicated in 967 women from ORCADES cohort (Orkney Complex Disease Study), and 6 of them were also associated in 845 men. A linear combination of IgG glycans and GlycA is also associated with presence of carotid (odds ratio, 1.55; 95% confidence interval, 1.25-1.93; P =7.5×10 -5 ) and femoral (odds ratio, 1.32; 95% confidence interval, 1.06-1.64; P =0.01) plaque in a subset of women with atherosclerosis data after adjustment for traditional risk factors. One specific glycosylation trait, GP18-the percentage of FA2BG2S1 glycan in total IgG glycans, was negatively correlated with very-low-density lipoprotein and triglyceride levels in serum and with presence of carotid plaque (odds ratio, 0.60; 95% confidence interval, 0.50-0.71; P =5×10 -4 )., Conclusions: We find molecular pathways linking IgG to arterial lesion formation. Glycosylation traits are independently associated with subclinical atherosclerosis. One specific trait related to the sialylated N-glycan is negatively correlated with cardiovascular disease risk, very-low-density lipoprotein and triglyceride serum levels, and presence of carotid plaque., (© 2018 The Authors.)

BackgroundMulti-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.ObjectivesTo discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.MethodsSummary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27).ResultsAcross the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes.ConclusionsThe discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

The notion that coronary atherosclerosis and its most severe phenotype, myocardial infarction (MI), are chronic inflammatory diseases is supported by several lines of evidence. Interleukins (ILs) are important mediators and modulators of inflammation. Specific polymorphisms in the genes encoding subunits of IL-23 ( IL-12B) and its receptor ( IL-23R) have recently been consistently found to be associated with chronic immune-mediated diseases. In this study, we explored the hypothesis that these variants also affect the risk of MI. We conducted a case–control association study on a cohort of 738 British Caucasian MI patients and 716 population controls. We tested four variants (rs11209026, rs7517847, rs1343151, rs10889677) of IL-23R and the A1188C polymorphism (rs3212227) of IL-12B. There was no association of any IL-23R (rs11209026, p = 0.82; rs7517847, p = 0.87; rs1343151, p = 0.85; rs10889677, p = 0.48) or IL-12B (rs3212227, p = 0.32) polymorphisms with MI. Stratification for age, gender and other cardiovascular risk factors did not affect the findings. These results indicate that unlike other chronic inflammatory diseases, the examined variants are unlikely to be major contributors to the pathogenesis of MI. [ABSTRACT FROM AUTHOR]

Abstract: Background: Leukotrienes are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway. Both experimental and clinical studies implicate the 5-lipoxygenase pathway in the pathophysiology of atherosclerosis. In a previous study, a microsatellite polymorphism in the 5-lipoxygenase gene promoter involving the binding site for the transcription factor Sp1, was associated with carotid intima media thickness (CIMT). Compared to subjects carrying the common allele, subjects carrying two variant alleles had significantly greater CIMT. Elevated CIMT is a risk factor for coronary events. In this study we investigated whether carriage of two variants alleles for the 5-lipoxygenase promoter polymorphism is associated with increased risk of myocardial infarction (MI). Methods: 1464 subjects, comprising 746 MI cases (under 65 years of age) and 718 controls, were genotyped for the 5-lipoxygenase microsatellite polymorphism by PCR amplification of the promoter region and allele discrimination by capillary electrophoresis. Results: The distribution of subjects grouped into those homozygote for the common allele, subjects carrying one variant allele, and subjects carrying two variant alleles was similar in cases and controls (cases: 66.9%/29.8%/3.3%, controls: 66.0%/29.4%/4.6%, p =0.48). The odds ratio for MI for subjects carrying two variant alleles compared to subjects carrying at least one common allele was 0.72 (95% CI: 0.42–1.22, p =0.22). The odds ratio was not affected by adjustment for other demographic risk factors. Conclusions: Despite their association with a marker of atherosclerosis, variant 5-lipoxygenase promoter genotypes are not a major risk factor for MI, at least in Caucasian subjects of Northern European origin. [Copyright &y& Elsevier]