Observational studies report that secretory phospholipase A2 (sPLA2) activity is a marker for coronary heart disease (CHD) risk, and activity measures are thought to represent the composite activity ...of sPLA2-IIA, -V, and -X. The aim of this study was to use genetic variants of PLA2G10, encoding sPLA2-X, to investigate the contribution of sPLA2-X to the measure of sPLA2 activity and coronary heart disease (CHD) risk traits and outcome.
Three PLA2G10 tagging single-nucleotide polymorphisms (rs72546339, rs72546340, and rs4003232) and a previously studied PLA2G10 coding single-nucleotide polymorphism rs4003228, R38C, were genotyped in a nested case: control cohort drawn from the prospective EPIC-Norfolk Study (2175 cases and 2175 controls). Meta-analysis of rs4003228 (R38C) and CHD was performed using data from the Northwick Park Heart Study II and 2 published cohorts AtheroGene and SIPLAC, providing in total an additional 1884 cases and 3119 controls. EPIC-Norfolk subjects in the highest tertile of sPLA2 activity were older and had higher inflammatory markers compared with those in the lowest tertile for sPLA2 activity. None of the PLA2G10 tagging single-nucleotide polymorphism nor R38C, a functional variant, were significantly associated with sPLA2 activity, intermediate CHD risk traits, or CHD risk. In meta-analysis, the summary odds ratio for R38C was odds ratio=0.97 (95% confidence interval, 0.77-1.22).
PLA2G10 variants are not significantly associated with plasma sPLA2 activity or with CHD risk.
Oxidation of low density lipoproteins is an initial step of atherogenesis that generates pro-inflammatory phospholipids, including platelet-activating factor (PAF) and its analogs. PAF is degraded by ...PAF-acetylhydrolase (PAF-AH), a circulating enzyme having both pro- and anti-inflammatory activities. PAF-AH activity has been postulated to be a risk factor for coronary artery disease (CAD); however, whether PAF-AH has a causal role or is simply a marker of risk is unclear. The aim of this study was to relate the variability of the genes encoding PAF-AH (PLA2G7) and the PAF-receptor (PTAFR) to the risk of CAD and its complications. All polymorphisms located in putatively functional regions were investigated in a prospective cohort of CAD patients (n=1314) and a group of healthy controls (n=485). The whole gene variability was investigated in relation to case–control status, prospective cardiovascular outcome and plasma PAF-AH levels by means of haplotype analyses. All analyses indicated an effect of the PLA2G7/A379V polymorphism independent of the other polymorphisms. The V379 allele was less frequent in CAD patients than in controls and was associated with a lower risk of future cardiovascular events, suggesting that this allele might be protective against the development of CAD. The V379 allele was also associated with a weak increase of plasma PAF-AH activity that was unlikely to explain the protective effect of the allele on risk. A more likely interpretation is that the A379V polymorphism might modify the enzyme function towards a more anti-atherogenic form. Polymorphisms of the PTAFR gene were not related to any phenotype.
Environmental and genetic correlates of inflammatory marker variability are incompletely understood. In the family-based Framingham Heart Study, we investigated heritability and candidate gene ...associations of systemic inflammatory biomarkers.
In offspring participants (n=3710), we examined 11 inflammatory biomarkers (CD40 ligand, C-reactive protein, intercellular adhesion molecule-1, interleukin-6, urinary isoprostanes, monocyte chemoattractant protein-1, myeloperoxidase, P-selectin, tumor necrosis factor-alpha, tumor necrosis factor receptor II, fibrinogen). Heritability and bivariate genetic and environmental correlations were assessed by Sequential Oligogenic Linkage Analysis routines in 1012 family members. We examined 1943 tagging single-nucleotide polymorphisms in 233 inflammatory pathway genes with >or=5 minor allele carriers using a general genetic linear model. Clinical correlates explained 2.4% (CD40 ligand) to 28.5% (C-reactive protein) of the variability in inflammatory biomarkers. Estimated heritability ranged from 10.9% (isoprostanes) to 44.8% (P-selectin). Most correlations between biomarkers were weak although statistically significant. A total of 45 single-nucleotide polymorphism-biomarker associations met the q-value threshold of 0.25. Novel top single-nucleotide polymorphisms were observed in ICAM1 gene in relation to intercellular adhesion molecule-1 concentrations (rs1799969, P=1.32 x 10(-8)) and MPO in relation to myeloperoxidase (rs28730837, P=1.9 x 10(-5)). Lowest P values for trans-acting single-nucleotide polymorphisms were observed for APCS with monocyte chemoattractant protein-1 concentrations (rs1374486, P=1.01 x 10(-7)) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36 x 10(-5)). Novel potential candidates (APCS, MPO) need to be replicated.
Our community-based data support the relevance of clinical and genetic factors for explaining variation in inflammatory biomarker traits.
The association between maternal folate intake and risk of nonsyndromic oral clefts has been studied among many populations with conflicting results. The methylenetetrahydrofolate reductase gene ...(MTHFR) plays a major role in folate metabolism, and several polymorphisms, including C677T, are common in European populations. Data from a French study (1998-2001) let us investigate the roles of maternal dietary folate intake and the MTHFR polymorphism and their interaction on the risk of cleft lip with/without cleft palate (CL/P) and cleft palate only (CP). We used both case-control (164 CL/P, 76 CP, 236 controls; 148, 59, 168 of whom, respectively, had an available genotype) and case-parent (143 CL/P and 56 CP families) study designs and distinguished the role of the child's genotype and maternally mediated effects on risks. This study observed a beneficial effect of mothers' dietary folate intake on their offspring's risk (odds ratio (OR)(< or = 230 microg/day) = ref; for CL/P, OR(230-314 microg/day) = 0.56, 95% confidence interval = 0.3-0.9, OR(>314 microg/day) = 0.64, 0.4-1.1; for CP, OR(230-314 microg/day) = 1.15, 0.6-2.2, OR(>314 microg/day) = 0.70, 0.3-1.4). We observed a reduced risk associated with the TT genotype of the child in the case-control analysis (OR(CC) = ref; for CL/P, OR(TT) = 0.54, 0.3-1.1; for CP, OR(TT) = 0.33, 0.1-1.0); this genotype, either fetal or maternal, was not statistically significant in the case-parent analysis. A frequency of TT genotype higher in our control group than previously reported in France can partly explain the risk reduction observed in case-control comparison. Interactions were not statistically significant. Stratified case-parent analysis showed, however, slight heterogeneity in the role of TT genotype according to folate intake. The modest sample size limits this study, which nonetheless provides new estimate of the possible impact of dietary folate intake and MTHFR polymorphism on oral clefts.
Carotid intima-media thickness (IMT) reflects generalized atherosclerosis and is predictive of future vascular events. Evidence exists that carotid IMT is heritable, and genetic studies can provide ...clues in the pathogenesis of atherosclerosis.
We recruited 470 white ischemic stroke patients, measured common carotid artery (CCA) IMT, and analyzed 54 polymorphisms with suspected roles in atherosclerosis.
Among the polymorphisms tested, the angiotensin-converting enzyme insertion/deletion, osteopontin (OPN) T-443C, monocyte chemoattractant protein-1 (MCP-1) G-927C, and MCP-1 A-2578G polymorphisms were associated with CCA-IMT in age-gender-adjusted analysis. In multivariate analysis, the association between the OPN and MCP-1 polymorphisms remained significant. The OPN-443C allele was associated with increased IMT in the dominant model (0.053 mm for the TC and CC genotypes; P=0.001). The MCP-1-927C allele was associated with increased IMT in the additive model (0.040 mm for each C allele; P=0.001), and the MCP-1-2578 G allele was associated with decreased IMT in the recessive model (0.088 mm for the GG genotype; P=0.002).
The OPN and MCP-1 genes, coding for 2 cytokines with known roles in atherosclerosis, may contribute to increased carotid IMT and warrant further study.
Tissue factor (TF) and its specific inhibitor, tissue factor pathway inhibitor (TFPI), are important contributors to the initiation of the coagulation process.
To compare plasma levels of soluble TF ...(sTF) and free-TFPI (f-TFPI) between patients with stable angina pectoris (SAP) and acute coronary syndrome (ACS) and to assess the impact of the two variables on long-term prognosis.
Patients with SAPs (n = 1146) and acute coronary syndrome (n = 523) from the AtheroGene study were included and followed for 2.3 years. Because of the strong impact of unfractionated heparin (UFH) on f-TFPI levels, but not on sTF levels, patients having received UFH before blood drawing were excluded from the analyses on f-TFPI (n = 226).
On admission, no significant differences in sTF levels were observed between SAP and ACS patients. By comparison to patients with stable angina, f-TFPI levels significantly increased in patients with acute unstable angina and further increased in patients presenting with non-ST-elevation myocardial infarction and ST-elevation myocardial infarction (P < 10(-4)). Among the 1669 individuals with a coronary artery disease, 56 died from a cardiovascular cause. In prospective analyses, high sTF levels were independently associated with an increased risk of cardiovascular death in individuals with ACS (fully adjusted hazard ratio associated with one quartile increase = 2.06; 95% confidence interval 1.24-3.45; P = 0.006) but not in those with SAP (hazard ratio = 1.07; 95% confidence interval 0.78-1.46; P = 0.67). In SAP and ACS patients, high f-TFPI levels were not independently associated with an increased risk of cardiovascular death.
Plasma sTF levels were predictive of cardiovascular mortality in individuals with ACS, whereas f-TFPI levels were associated with the severity of myocardial damage on admission but were not independently related to outcome.
P-selectin (SELP) and its counter-receptor, P-selectin glycoprotein ligand-1 (PSGL-1), play key role in the transient attachment of leukocytes to endothelial cells predisposing to coronary heart ...disease (CHD). In the current report, 293 angiographically proven CHD patients and 327 age, gender, and race-matched controls were included. Our aim was to evaluate the contribution to CHD of the following SNPs: C-2123G, G-1969A and T715P in SELP, Met62Ile and the VNTR variants in
PSGL
-
1
gene in a North African population from Tunisia. While there were no significant differences in the distribution of SELP or PSGL-1 alleles or genotypes between patients and controls, a trend for a significant association of the C-2123G genotypes distribution with incident CHD was observed (
P
= 0.06). Assuming an additive model of transmission, the risk was 74% higher among subjects carrying the GG genotypes in comparison to those carrying the CC genotype (OR = 1.74 1.01–2.98,
P
= 0.04) and 80% higher in the recessive model (OR = 1.80 1.08–3.01,
P
= 0.02). Haplotype analysis did not identify any specific SELP or PSGL-1 haplotypes to be associated with CHD. The present study demonstrated no evidence of association between individual SELP or PSGL-1 SNPs or haplotypes with incident CHD. However, this study replicates absence of association of the mostly studied SNP, T715P, previously reported in individuals with African origin.
Body mass index, presence of diabetes mellitus, systolic blood pressure, LDL-cholesterol, and HDL-cholesterol were similar in the total ECTIM case population and the 366 cases selected for this study ...(data not shown). A 2nd model was adjusted for country and for established cardiovascular risk factors (smoking habits, body mass index, LDL-cholesterol, HDL-cholesterol, diabetes mellitus, systolic blood pressure).
Background Bariatric surgery is associated to improvements in obesity-associated comorbidities thought to be mediated by a decrease of adipose inflammation. However, the molecular mechanisms behind ...these beneficial effects are poorly understood. Methodology/Principal Findings We analyzed RNA-seq expression profiles in adipose tissue from 22 obese women before and 3 months after surgery. Of 15,972 detected genes, 1214 were differentially expressed after surgery at a 5% false discovery rate. Upregulated genes were mostly involved in the basal cellular machinery. Downregulated genes were enriched in metabolic functions of adipose tissue. At baseline, 26 modules of coexpressed genes were identified. The four most stable modules reflected the innate and adaptive immune responses of adipose tissue. A first module reflecting a non-specific signature of innate immune cells, mainly macrophages, was highly conserved after surgery with the exception of DUSP2 and CD300C. A second module reflected the adaptive immune response elicited by T lymphocytes; after surgery, a disconnection was observed between genes involved in T-cell signaling and mediators of the signal transduction such as CXCR1, CXCR2, GPR97, CCR7 and IL7R. A third module reflected neutrophil-mediated inflammation; after surgery, several genes were dissociated from the module, including S100A8, S100A12, CD300E, VNN2, TUBB1 and FAM65B. We also identified a dense network of 19 genes involved in the interferon-signaling pathway which was strongly preserved after surgery, with the exception of DDX60, an antiviral factor involved in RIG-I-mediated interferon signaling. A similar loss of connection was observed in lean mice compared to their obese counterparts. Conclusions/Significance These results suggest that improvements of the inflammatory state following surgery might be explained by a disruption of immuno-inflammatory cascades involving a few crucial molecules which could serve as potential therapeutic targets.
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