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Background: The phagocytic enzyme myeloperoxidase (MPO) acts as a front-line defender against microorganisms. However, increased MPO levels have been found to be associated with complex and calcified atherosclerotic lesions and incident cardiovascular disease. Therefore, this study aimed to investigate a predictive role of MPO, a biomarker of inflammation and oxidative stress, for total and cardiovascular mortality in patients referred to coronary angiography.
Methods and results: MPO plasma concentrations along with eight MPO polymorphisms were determined in 3036 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up 7.75 years). MPO concentrations were positively associated with age, diabetes, smoking, markers of systemic inflammation (interleukin-6, fibrinogen, C-reactive protein, serum amyloid A) and vascular damage (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) but negatively associated with HDL-cholesterol and apolipoprotein A-I. After adjustment for cardiovascular risk factors MPO concentrations in the highest versus the lowest quartile were associated with a 1.34-fold risk (95% CI: 1.09–1.67) for total mortality. In the adjusted model the hazard ratio for cardiovascular mortality in the highest MPO quartile was 1.42 (95% CI: 1.07–1.88). Five MPO polymorphisms were positively associated with MPO concentrations but not with mortality. Using Mendelian randomization, we did not obtain evidence for a causal association of MPO with either total or cardiovascular mortality.
Conclusions: MPO concentrations but not genetic variants at the MPO locus are independently associated with risk for total and cardiovascular mortality in coronary artery disease patients.
Background Heme oxygenase-1 is an inducible cytoprotective enzyme which handles oxidative stress by generating anti-oxidant bilirubin and vasodilating carbon monoxide. A (GT)n dinucleotide repeat and a -413A>T single nucleotide polymorphism have been reported in the promoter region of HMOX1 to both influence the occurrence of coronary artery disease and myocardial infarction. We sought to validate these observations in persons scheduled for coronary angiography. Methods We included 3219 subjects in the current analysis, 2526 with CAD including a subgroup of CAD and MI (n = 1339) and 693 controls. Coronary status was determined by coronary angiography. Risk factors and biochemical parameters (bilirubin, iron, LDL-C, HDL-C, and triglycerides) were determined by standard procedures. The dinucleotide repeat was analysed by PCR and subsequent sizing by capillary electrophoresis, the -413A>T polymorphism by PCR and RFLP. Results In the LURIC study the allele frequency for the -413A>T polymorphism is A = 0,589 and T = 0,411. The (GT)n repeats spread between 14 and 39 repeats with 22 (19.9%) and 29 (47.1%) as the two most common alleles. We found neither an association of the genotypes or allelic frequencies with any of the biochemical parameters nor with CAD or previous MI. Conclusion Although an association of these polymorphisms with the appearance of CAD and MI have been published before, our results strongly argue against a relevant role of the (GT)n repeat or the -413A>T SNP in the HMOX1 promoter in CAD or MI.
Background The role of the Fcgamma receptor IIa (FcgammaRIIa), a receptor for C-reactive protein (CRP), the classical acute phase protein, in atherosclerosis is not yet clear. We sought to investigate the association of FcgammaRIIa genotype with risk of coronary heart disease (CHD) in two large population-based samples. Methods FcgammaRIIa-R/H131 polymorphisms were determined in a population of 527 patients with a history of myocardial infarction and 527 age and gender matched controls drawn from a population-based MONICA- Augsburg survey. In the LURIC population, 2227 patients with angiographically proven CHD, defined as having at least one stenosis [greater than or equal to]50%, were compared with 1032 individuals with stenosis <50%. Results In both populations genotype frequencies of the FcgammaRIIa gene did not show a significant departure from the Hardy-Weinberg equilibrium. FcgammaRIIa R(-131)->H genotype was not independently associated with lower risk of CHD after multivariable adjustments, neither in the MONICA population (odds ratio (OR) 1.08; 95% confidence interval (CI) 0.81 to 1.44), nor in LURIC (OR 0.96; 95% CI 0.81 to 1.14). Conclusion Our results do not confirm an independent relationship between FcgammaRIIa genotypes and risk of CHD in these populations.
Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.
Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.
Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).
Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.
Using apoE phenotyping by immunoblotting and apoE genotyping we identified four heterozygous carriers of a rare apolipoprotein (apo) E2 variant, apoE2 (Arg136 → Cys). ApoE2 (Arg136 → Cys) was not distinct from apoE2 (Arg158 → Cys) by phenotyping, but produced a unique pattern of bands on CfoI restriction typing of a 244 bp apoE gene fragment. Two of the four apoE2 (Arg136 → Cys)/3 heterozygotes had elevated triglycerides, two were normolipidemic. The composition of very low density lipoproteins (VLDL) was normal in each of the four apoE2 (Arg136 → Cys) carriers, regardless of the triglyceride concentrations. None of the apoE2 (Arg136 → Cys) carriers displayed a broad β-band and none revealed β-migrating particles in the VLDL. The two hypertriglyceridemic carriers of apoE2 (Arg136 → Cys) were, therefore, classified as having type IV rather than type III hyperlipoproteinemia. LDL receptor binding activities were studied using recombinant apoE loaded to dimyristoylphosphatidylcholine (DMPC) vesicles and to VLDL and from an apoE-deficient individual. LDL receptor binding of apoE2 (Arg136 → Cys) was 14% of apoE3 and was thus higher than that of apoE2 (Arg158 → Cys). Both apoE2 (Arg136 → Cys) and apoE2 (Arg158 → Cys) displayed substantial heparin binding (61 and 53% of apoE3, respectively). As the dominant apoE variants known so far are characterized by more pronounced reductions of heparin binding, we suggest that apoE2 (Arg136 → Cys) is not associated with dominant expression of type III hyperlipoproteinemia. These findings lend support to the concept that apoE variants predisposing to dominant type III hyperlipoproteinemia differ from recessive mutations by a more severe defect in heparin binding.—März, W., M. M. Hoffmann, H. Scharnagl, E. Fisher, M. Chen, M. Nauck, G. Feussner, and H. Wieland. Apolipoprotein E2 (Arg136 → Cys) mutation in the receptor binding domain of apoE is not associated with dominant type III hyperlipoproteinemia.
Changes in the balance of cholesterol absorption and synthesis and moderately elevated plasma plant sterols have been suggested to be atherogenic. Measuring cholestanol, lathosterol, campesterol, and sitosterol, we investigated the relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease (CAD) in 2,440 participants of the Ludwigshafen Risk and Cardiovascular health (LURIC) study. The coronary status was determined by angiography, and the severity of CAD was assessed by the Friesinger Score (FS). An increase in the ratio of cholestanol to cholesterol was associated with high FS (P = 0.006). In contrast, a high ratio of lathosterol to cholesterol went in parallel with low FS (P < 0.001). Whereas the campesterol to cholesterol ratio significantly correlated with the FS (P = 0.026), the relationship of the sitosterol to cholesterol ratio with the FS did not reach statistical significance in the whole group. Increased campesterol, sitosterol, and cholestanol to lathosterol ratios were associated high FS (P < 0.001). To conclude, there is a modest association of high cholesterol absorption and low cholesterol synthesis with an increased severity of CAD. An atherogenic role of plasma plant sterols themselves, however, seems unlikely in subjects without sitosterolaemia.