Fibrinogen has consistently been recognized as an independent predictor of myocardial infarction (MI). Multiple mechanisms link fibrinogen to MI; therefore disentangling the factors underlying variation in plasma fibrinogen concentration is essential. Candidate regions in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes were screened for single nucleotide polymorphisms (SNPs). Several novel SNPs were detected in the FGG and FGA genes in addition to the previously known SNPs in the fibrinogen genes. Tight linkage disequilibrium extending over various physical distances was observed between most SNPs. Consequently, eight SNPs were chosen and determined in 377 postinfarction patients and 387 healthy individuals. None of the SNPs were associated with plasma fibrinogen concentration or MI. Haplotype analyses revealed a consistent pattern of haplotypes associated with variation in risk of MI. Of the four haplotypes inferred using the FGA -58G>A and FGG 1299 +79T>C SNPs, the most frequent haplotype, FGG-FGA*1 (prevalence 46.6%), was associated with increased risk of MI (OR 1.51; 95%CI 1.18, 1.93), whereas the least frequent haplotype, FGG-FGA*4 (11.8%), was associated with lower risk of MI (OR 0.79 95%CI 0.64, 0.98). In conclusion, fibrinogen haplotypes, but not SNPs in isolation, are associated with variation in risk of MI.
Coagulation factor VIII, von Willebrand factor, antithrombin, fibrinogen, plasminogen activator capacity, and inhibitors of fibrinolysis, including a recently discovered fast inhibitor of tissue plasminogen activator, were measured three to six months after myocardial infarction in 116 male and 32 female patients aged less than 45 and in 136 age and sex matched random controls. Plasma concentrations of fibrinogen and the fast inhibitor of tissue plasminogen activator were raised in male patients (with or without correction for orosomucoid levels, blood group distribution, tobacco and alcohol consumption, and weight/height index) and plasminogen activator capacity was reduced. In female patients the concentrations of factor VIII, von Willebrand factor, the fast inhibitor of tissue plasminogen activator, alpha 2-antiplasmin, and C1 inhibitor were significantly increased. The increase in factor VIII concentrations depended strongly on a persisting inflammatory response. Multivariate analysis indicated that a combination of fibrinogen and tissue plasminogen activator inhibitor concentrations gave the best independent discrimination between male patients and controls. For female patients the best combination was von Willebrand factor and tissue plasminogen activator inhibitor. Male patients with multiple vessel atheromatosis at coronary angiography had higher fibrinogen concentrations than those with atheromatosis of a single vessel. Atheromatosis was defined as sharp-edged, plaque-like, or irregular indentations, often multiple, into the vessel lumen without features suggesting fibromuscular hyperplasia.
Abstract Hypertension is a leading cause of premature death affecting more than a billion individuals worldwide. Here we report on the genetic determinants of blood pressure (BP) traits (systolic, diastolic, and pulse pressure) in the largest single-stage genome-wide analysis to date (N = 1,028,980 European-descent individuals). We identified 2,103 independent genetic signals (P < 5x10− 8) for BP traits, including 113 novel loci. These associations explain ~ 40% of common SNP heritability of systolic and diastolic BP. Comparison of top versus bottom deciles of polygenic risk scores (PRS) based on these results reveal clinically meaningful differences in BP (12.9 mm Hg for systolic BP, 95% CI 11.5–14.2 mm Hg, p = 9.08×10− 73) and hypertension risk (OR 5.41; 95% CI 4.12 to 7.10; P = 9.71×10− 33) in an independent dataset. Compared with the area under the curve (AUC) for hypertension discrimination for a model with sex, age, BMI, and genetic ancestry, adding systolic and diastolic BP PRS increased discrimination from 0.791 (95% CI = 0.781–0.801) to 0.814 (95% CI = 0.805–0.824, ∆AUC = 0.023, P = 2.27x10− 22). Our transcriptome-wide association study detected 2,793 BP colocalized associations with genetically-predicted expression of 1,070 genes in five cardiovascular tissues, of which 500 are previously unreported for BP traits. These findings represent an advance in our understanding of hypertension and highlight the role of increasingly large genomic studies for development of more accurate PRS, which may inform precision health research.
Abstract. Objectives. Matrix metalloproteinase‐3 (MMP‐3) is implicated in the formation of atherosclerotic plaques, and the MMP‐3 −1612 5A/6A polymorphism is associated with myocardial infarction (MI) and stable coronary artery disease (CAD). The present study examined whether the −1612 5A/6A polymorphism in the promoter region of the MMP‐3 gene influences serum concentrations of MMP‐3 and whether serum concentrations of MMP‐3 are related to extent of coronary atherosclerosis and risk of MI. Design and subjects. This case–control study was conducted in three hospitals in the northern part of Stockholm. A total of 755 MI patients aged below 60 were screened, 433 entered and 387 completed the study. Three hundred and eighty‐seven sex‐ and age‐matched control subjects were recruited from the general population of the same county. Methods. The MMP‐3 genotype was determined by Pyrosequencing TM and the serum MMP‐3 concentration was quantified with an immunoassay. Severity and extension of CAD was assessed by quantitative coronary angiography in a subgroup of patients ( n = 243). Results. Patients had lower serum MMP‐3 concentration than controls. There was a strong association between MMP‐3 −1612 5A/6A genotype and serum concentrations of MMP‐3. The presence of one or two copies of the 6A‐allele was associated with a graded increase in serum MMP‐3. In female patients there was an inverse correlation ( r = −0.39, P < 0.05) between serum MMP‐3 concentration and plaque area. Conclusion. In conclusion, the serum concentration of MMP‐3 is influenced by MMP‐3 −1612 5A/6A genotype and associated with MI.
Association studies were carried out in a sample of 86 patients from Sweden who had survived a myocardial infarction (MI) at a young age and 93 age-matched healthy individuals, to compare the impact of polymorphisms at the apolipoprotein (apo) AI-CIII-AIV gene cluster on among-individual differences in plasma lipid and lipoprotein traits, the five high density lipoprotein (HDL) subclasses (2b to 3c), lipoprotein lipase (LPL) activity and presence and progression of atherosclerosis. Individuals were genotyped for four polymorphisms; 5'apoAI (G/A-75), 3'apoAI (PstI; P +/-), apoCIII (C/T1100) and apoCIII (PvuII; V +/-), using PCR-based techniques. Allele frequencies were similar in healthy individuals and patients (frequencies of alleles in combined population: 5'apoAI-A-75 = 0.14, 3'apoAI-P- = 0.05, apoCIII-T1100 = 0.27 and apoCIII-V- = 0.18). In the healthy individuals, levels of low density lipoprotein (LDL) triglycerides were significantly associated with genotypes of the apoCIII-PvuII polymorphism (p = 0.02), but no other associations were found between lipids or HDL subclasses and single polymorphisms in the apoAI-CIII-AIV gene cluster. Levels of triglycerides and very low density lipoprotein (VLDL) triglycerides were significantly higher in the presence of the haplotype defined by the presence of apoCIII-T1100 and common alleles of the other three polymorphisms, explaining 5.8% and 7.8% (p = 0.03 and 0.01), respectively, of sample variance. In the patients, no associations were found between lipids or HDL subclasses and variation at the apoAI-CIII-AIV gene cluster. Associations were also examined between levels of HDL subclasses and variation at the apoE (common isoforms), apoB (signal peptide and XbaI polymorphisms) and lipoprotein lipase (PvuII, HindIII and Serine447/Stop polymorphisms) gene loci. In the patient group only, levels of protein in HDL2b, HDL2a and HDL3b subclasses were significantly associated with genotypes of the LPL-HindIII polymorphism (22.1, 19.3 and 11.4%, respectively, of sample variance; p < 0.05). Finally, associations were examined between genotypes at the apoAI-CIII-AIV gene cluster and the extent of coronary atherosclerosis. Global severity of atherosclerosis at the first angiography was weakly associated with genotypes of the apoCIII-C/T1100 polymorphism, presence of the T1100 allele being associated with 53% lower median score (1.6 vs 0.75; p = 0.09).(ABSTRACT TRUNCATED AT 400 WORDS)
This study was performed in order to assess the optimal quantitative criteria of transient defects to detect coronary stenosis with a diameter reduction of ≥ 50% in areas remote from myocardial infarction (MI), and in order to evaluate the presence of transient defects, indicating residual ischemia, in infarcted regions. Ninety-four men aged 30–44 years were examined by planar imaging thallium-201 scintigraphy following exercise and coronary angiography after MI. The coronary angiograms were scored with respect to the presence of distinct stenosis in 15 proximal segments. Transient thallium defects were quantitatively assessed and defined as the difference in relative uptake of thallium-201 at 4 h after and immediately after exercise. We found that the optimal criteria of remote transient defects in anterior regions corresponded to a sensitivity of 59% and a specificity of 52% for left anterior descending coronary artery (LAD) stenoses, in lateral regions to 81 and 60% for left circumflex coronary artery (LCX) stenoses and in inferior regions to 82 and 61% for right coronary artery stenoses. Subsequently the same criteria were applied to assess the number of transient defects in myocardial segments with a decreased (<0.80) relative uptake of thallium 4 h after exercise. Our results showed that transient defects were present in anterior regions with permanent defects in 32 out of 42 patients. Of these 32 patients, 21 had an occlusion of the corresponding coronary artery and 9 had a 50–99% stenosis. In inferior regions, 17 out of 35 patients with permanent defects had transient defects. Of these 17 patients, 11 had a coronary occlusion and 1 patient had a significant stenosis. Among the 11 patients with permanent defects in the lateral wall of the left ventricle, 3 had transient defects; 1 of these had an occlusion and 2 significant stenoses. In conclusion, our results showed that transient defects, as assessed by quantitative analysis of planar imaging thallium scintigraphy after exercise, showed a fairly good sensitivity in detecting significant stenoses remote from infarction in both the right and the LCX, but a relatively low sensitivity for stenoses in the LAD. In addition, transient defects were frequently observed in regions with permanent defects, suggesting a high rate of residual ischemia in infarcted zones.
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