Objectives Early identification of myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation. Background The aim of the current ...investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to cardiac troponin in early evaluation of patients with suspected myocardial infarction. Methods Between January 2007 and July 2008, patients with suspected acute coronary syndrome were consecutively enrolled in this multicenter study. Copeptin, troponin T (TnT), myoglobin, and creatine kinase-myocardial band were determined at admission and after 3 and 6 h. Results Of 1,386 (66.4% male) enrolled patients, 299 (21.6%) had the discharge diagnosis of acute myocardial infarction, 184 (13.3%) presented with unstable angina, and in 903 (65.2%) an acute coronary syndrome could be excluded. Combined measurement of copeptin and TnT on admission improved the c-statistic from 0.84 for TnT alone to 0.93 in the overall population and from 0.77 to 0.9 in patients presenting within 3 h after chest pain onset (CPO) (p < 0.001). In this group the combination of copeptin with a conventional TnT provided a negative predictive value of 92.4%. Conclusions In triage of chest pain patients, determination of copeptin in addition to troponin improves diagnostic performance, especially early after CPO. Combined determination of troponin and copeptin provides a remarkable negative predictive value virtually independent of CPO time and therefore aids in early and safe rule-out of myocardial infarction.
Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial ...infarction.
In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission.
For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve AUC, 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. With the use of the sensitive troponin I assay (cutoff value, 0.04 ng per milliliter) on admission, the clinical sensitivity was 90.7%, and the specificity was 90.2%. The diagnostic accuracy was virtually identical in baseline and serial samples, regardless of the time of chest-pain onset. In patients presenting within 3 hours after chest-pain onset, a single sensitive troponin I assay had a negative predictive value of 84.1% and a positive predictive value of 86.7%; these findings predicted a 30% rise in the troponin I level within 6 hours. A troponin I level of more than 0.04 ng per milliliter was independently associated with an increased risk of an adverse outcome at 30 days (hazard ratio, 1.96; 95% confidence interval, 1.27 to 3.05; P=0.003).
The use of a sensitive assay for troponin I improves early diagnosis of acute myocardial infarction and risk stratification, regardless of the time of chest-pain onset.
Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits ...and have a critical role in physiological and disease processes.
To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself.
This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.
Interleukin (IL)-18 plays a key role in atherosclerosis and its complications. The present study investigated the genetic variability of 4 genes of the IL-18 system-IL18, IL18R1, IL18RAP, and ...IL18BP-in relation to circulating IL-18 levels and cardiovascular mortality.
Twenty-two polymorphisms were genotyped in 1288 patients with coronary artery disease prospectively followed up during a median period of 5.9 years. The end point was death from cardiovascular causes (n=142). Baseline IL-18 levels were predictive of cardiovascular deaths occurring during < or =4 years of follow-up (HR=2.96, 95% CI 1.54 to 5.70, P=0.001 for the top compared with the bottom quartile) but not of later deaths. Haplotypes of the IL18 gene were associated with IL-18 levels (P=0.002) and cardiovascular mortality (P=0.006) after adjustment for cardiovascular risk factors. The same haplotype was associated with both a 9% lowering effect on IL-18 levels and a protective effect on risk (HR=0.57, 95% CI 0.36 to 0.92). IL18 haplotypes explained only 2% of IL-18 variability. Adjustment for baseline IL-18 levels abolished the association of haplotypes with cardiovascular risk. The haplotype associated with phenotypes was the only one carrying the minor allele of the IL18/A+183G polymorphism located in the 3'untranslated region and potentially affecting mRNA stability. The other genes of the system were not related to IL-18 levels or cardiovascular outcome.
Variations of the IL18 gene consistently influence circulating levels of IL-18 and clinical outcome in patients with coronary artery disease, which supports the hypothesis of a causal role of IL-18 in atherosclerosis and its complications.
The aim of this study was to investigate the influence of
APOA5 variants on fasting lipids and to the response to both an oral fat tolerance test (OFTT) and an oral glucose tolerance test (OGTT). The ...association of two
APOA5 SNPs S19W (SNP5), −1131T>C (SNP3) and an
APOA4/A5 intergenic SNP −12238T>C (SNP4) were examined in healthy young men (
n=774) who had undergone both an OFTT and an OGTT. Both −1131T>C and S19W rare alleles were associated with triglyceride (TG)-raising effects (11%,
P=0.008; 21% (in cases),
P<0.026, respectively) and showed additive effects on TG. None of the variants influenced the responsiveness to the OFTT after correcting for baseline TG. Homozygosity for the −12238T>C rare allele was associated with higher waist to hip ratio (
P<0.0006), systolic blood pressure (
P=0.012) and AUC and peak of insulin after OGTT (
P=0.003 and
P=0.027, respectively), traits that define the metabolic syndrome. Our results strongly support the role of
APOA5 in determining plasma TG levels in an age-independent manner and highlight the importance of the
APOC3/A4/A5 gene cluster in both TG and metabolic homeostasis.
A common polymorphism has been described in the methylenetetrahydrofolate reductase (MTHFR) gene, substituting an alanine (A) for a valine (V), where the V allele results in a thermolabile enzyme ...with reduced activity. This polymorphism is easily detectable by PCR amplification and digestion with
HinfI restriction enzyme. We describe the use of the MADGE high throughput genotyping system for rapid typing of this polymorphism. Seven hundred and eighty five individuals participating in the European Atherosclerosis Research Study II (EARS II), aged 22–25 from 14 universities in 12 countries across Europe were genotyped for this polymorphism. The frequency of the V allele was 0.32 overall (95% CI; 0.30–0.35), but was significantly lower in the Baltic countries (0.23; 95% CI; 0.19–0.28) compared with the other regions of Europe (0.37; 95% CI; 0.32–0.38) (
P<0.001). Individuals homozygous for the V allele had statistically significant (
P<0.001) higher plasma homocysteine (16.5
μmol/l) compared with those heterozygous for an A allele (10.4
μmol/l) or homozygous for an A allele (10.0
μmol/l). This effect was seen in all countries and regions of Europe. Mean plasma homocysteine levels were significantly higher in the South compared to the Baltic, UK and Middle regions (
P=0.001), but this difference was not explained by the difference in the frequency of the V allele in the samples. This polymorphism explained 12.3% of the total sample variance in plasma homocysteine, other measured factors (smoking, alcohol consumption, systolic blood pressure, physical activity) explained 0.7%. This study demonstrates the large and consistent impact of the thermolabile MTHFR variant on plasma homocysteine levels in different European populations, and shows a regional difference in the levels of homocysteine that must be explained by other genetic or environmental factors.
By regulating the cellular cholesterol efflux from peripheral cells to high-density lipoprotein, the ABCA1 protein is suspected to play a key role in lipid homeostasis and atherosclerosis. Twenty-six ...polymorphisms of the ABCA1 gene were genotyped and tested for association with plasma levels of ApoA1 and myocardial infarction (MI) in the ECTIM study.
In addition to single-locus analysis, a systematic exploration of all possible haplotype effects was performed, with this exploration being performed on a minimal set of "tag" polymorphisms that define the haplotype structure of the gene. Two polymorphisms were associated with plasma levels of ApoA1, 1 in the promoter (C-564T) and 1 in the coding (R1587K) regions, whereas only 1 polymorphism (R219K) was associated with the risk of MI. However, no haplotype effect was detected on ApoA1 variability or on the risk of MI.
ABCA1 gene polymorphisms but not haplotypes are involved in the variability of plasma ApoA1 and the susceptibility to coronary artery disease.
The matrix Gla protein (MGP) is an important inhibitor of vessel and cartilage calcification that is strongly expressed in human calcified, atherosclerotic plaques and could modulate plaque ...calcification and coronary heart disease risk. Using a genetic approach, we explored this possibility by identifying polymorphisms of the MGP gene and testing their possible association with myocardial infarction (MI) and plaque calcification. Eight polymorphisms were identified in the coding and 5'-flanking sequences of the MGP gene. All polymorphisms were investigated in 607 patients with MI and 667 control subjects recruited into the ECTIM Study (Etude Cas-Témoins de l'Infarctus du Myocarde) and in 717 healthy individuals with echographically assessed arterial calcification and atherosclerosis who were participating in the AXA Study. In the ECTIM Study, alleles and genotypes were distributed similarly in patients and controls in the whole study group; in only 1 subgroup of subjects defined as being at low risk for MI were the concordant A-7 and Ala 83 alleles more frequent in patients with MI than in controls (P<0.003). In the AXA Study among subjects with femoral atherosclerosis, the same alleles were more common in the presence than the absence of plaque calcification (P<0.025). The other MGP polymorphisms were not associated with any investigated clinical phenotype. Transient transfection experiments with allelic promoter-reporter gene constructs and DNA-protein interaction assays were carried out to assess possible in vitro functionality of the promoter variants detected at positions -814, -138, and -7 relative to the start of transcription. When compared with the -138 T allele, the minor -138 C: allele consistently conferred a reduced promoter activity of -20% (P<0.0001) in rat vascular smooth muscle cells and of -50% (P<0.004) in a human fibroblast cell line, whereas the other polymorphisms, including -7, displayed no evidence of in vitro functionality. We conclude that the A-7 or Ala 83 alleles of the MGP gene may confer an increased risk of plaque calcification and MI; however, the observed relationships are weak or limited to subgroups of patients and therefore need confirmation.
G/T Substitution in Intron 1 of the UNC13B Gene Is Associated With Increased Risk of Nephropathy in Patients With Type 1 Diabetes
David-Alexandre Trégouet 1 ,
Per-Henrik Groop 2 3 ,
Steven McGinn 4 ,
...Carol Forsblom 2 3 ,
Samy Hadjadj 5 6 ,
Michel Marre 7 8 ,
Hans-Henrik Parving 9 ,
Lise Tarnow 10 ,
Ralph Telgmann 11 ,
Tiphaine Godefroy 1 ,
Viviane Nicaud 1 ,
Rachel Rousseau 1 ,
Maikki Parkkonen 3 ,
Anna Hoverfält 3 ,
Ivo Gut 4 ,
Simon Heath 4 ,
Fumihiko Matsuda 4 ,
Roger Cox 12 ,
Gbenga Kazeem 13 ,
Martin Farrall 13 ,
Dominique Gauguier 13 ,
Stefan-Martin Brand-Herrmann 11 ,
François Cambien 1 ,
Mark Lathrop 4 ,
Nathalie Vionnet 1 and
for the EURAGEDIC Consortium
1 INSERM, Paris, France, and Pierre and Marie Curie-Paris VI University, Paris, France
2 Helsinki University Central Hospital, Department of Medicine, Division of Nephrology, Helsinki, Finland
3 Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum, Helsinki, Finland
4 CEA/Institute of Genomics-National Genotyping Center, Evry, France
5 CHU Poitiers, Department of Diabetology, Poitiers, France
6 INSERM U927, CHU Poitiers, Poitiers, France
7 Assistance Publique des Hôpitaux de Paris, Centre Hospitalier Universitaire Bichat-Claude Bernard, Paris, France
8 Université Paris, INSERM U695, Paris, France
9 University Hospital of Copenhagen, Rigshospitalet, Department of Medical Endocrinology, Copenhagen, Denmark
10 Steno Diabetes Center, Copenhagen, Denmark
11 Leibniz Institute for Arteriosclerosis Research, Department of Molecular Genetics of Cardiovascular Disease, University of
Muenster, Muenster, Germany
12 Mammalian Research Council, Mammalian Genetics Unit, Harwell, U.K
13 Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, U.K
Corresponding author: Nathalie Vionnet, vionnet{at}cng.fr
Abstract
OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors.
The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify
nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy.
RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search.
A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent
albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations.
RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers
fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three
populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29–2.19) ( P = 1.0 × 10 −4 ). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR
of 1.63 95% CI 1.30–2.05, P = 2.3 × 10 −5 ).
CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of
nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies
are needed to clarify the role of UNC13B in nephropathy.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 8, 2008.
Received January 18, 2008.
DIABETES
Among secreted phospholipases A2 (sPLA2s), human group X sPLA2 (hGX sPLA2) is emerging as a novel attractive therapeutic target due to its implication in inflammatory diseases. To elucidate whether ...hGX sPLA2 plays a causative role in coronary artery disease (CAD), we screened the human
PLA2G10
gene to identify polymorphisms and possible associations with CAD end-points in a prospective study, Athero
Gene
. We identified eight polymorphisms, among which, one non-synonymous polymorphism R38C in the propeptide region of the sPLA2. The T-512C polymorphism located in the 5′ untranslated region was associated with a decreased risk of recurrent cardiovascular events during follow-up. The functional analysis of the R38C polymorphism showed that it leads to a profound change in expression and activity of hGX sPLA2, although there was no detectable impact on CAD risk. Due to the potential role of hGX sPLA2 in inflammatory processes, these polymorphisms should be investigated in other inflammatory diseases.
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