Common functional variants of APOA5 and GCKR accumulate gradually in association with triglyceride increase in metabolic syndrome patients.

The common functional variants of the apolipoprotein A5 (APOA5) and the glucokinase regulatory protein genes (GCKR) have been shown to associate with increased fasting triglyceride (TG) levels. Albeit the basic association has been extensively investigated in several populations of different origin, less is known about quantitative traits of them. In our study accumulation rates of four APOA5 (T-1131, IVS3 + G476A, T1259C and C56G) and two GCKR (C1337T and rs780094) functional SNPs were analyzed in patients stratified into four TG quartile groups. Randomly selected 325 metabolic syndrome patients were separated into four quartile (q) groups based on the TG levels as follows q1: TG <1.38 mmol/l; q2: 1.38-1.93 mmol/l; q3: 1.94-2.83 mmol/l; and q4: TG >2.83 mmol/l. We observed significant stepwise increase of prevalence rates of minor allele frequencies in the four plasma TG quartiles for three APOA5 SNPs: -1131C (q1: 4.94%; q2: 8.64%; q3: 11.6%; q4: 12.3%), IVS3 + 476A (q1: 4.32%; q2: 7.4%; q3: 10.36%; q4: 11.1%), and 1259C (q1: 4.94%; q2: 7.41%; q3: 10.4%; q4: 11.7%). The haplotype analysis revealed, that the frequency of APOA5*2 haplotype gradually increased in q2, q3 and q4 (q1: 9.87%; q2: 14.8%; q3: 18.3%; q4: 21%). The distribution of the homozygotes of the two analyzed GCKR variants resembled to the APOA5 pattern. Contrary to the hypothetically predictable linear association coming from the current knowledge about the APOA5 and GCKR functions, the findings presented here revealed a unique, TG raise dependent gradual accumulation of the functional variants of in MS patients. Thus, the findings of the current study serve indirect evidence for the existence of rare APOA5 and GCKR haplotypes in metabolic syndrome patients with higher TG levels, which contribute to the complex lipid metabolism alteration in this disease.

Stepwise positive association between APOA5 minor allele frequencies and increasing plasma triglyceride quartiles in random patients with hypertriglyceridemia of unclarified origin.

Apolipoprotein A5 (ApoA5) gene and its protein product play a central role in the complex regulation of circulating triglyceride levels in humans. Naturally occurring variants of the apolipoprotein A5 gene have been associated with increased triglyceride levels and have been found to confer risk for cardiovascular diseases. In our study, four polymorphisms, the T-1131C, IVS3+G476A, T1259C, and C56G alleles of APOA5 were analyzed in a total of 436 patients by polymerase chain reaction-restriction fragment length polymorphism methods. The randomly selected patients were classified into four quartile (q) groups based on triglyceride levels (q1: TG<1.31 mmol/l; q2: 1.31-2.90 mmol/l; q3: 2.91-4.85 mmol/l; q4: TG>4.85 mmol/l). We observed significant stepwise increasing association between the four APOA5 minor allele carrier frequencies and plasma triglyceride quartiles: -1131C (q1: 4.44%; q2: 8.95%; q3: 12.9%; q4: 20.6%), IVS3 + 476A (q1: 4.44%; q2: 5.79%; q3: 11.1%; q4: 19.7%), 1259C (q1: 4.44%; q2: 6.84%; q3: 11.1%; q4: 20.6%) and 56G (q1: 5.64%; q2: 6.31%; q3: 11.16%; q4: 11.9%). The serum total cholesterol and high density lipoprotein-cholesterol levels also showed allele-dependent differences in the quartiles. The findings presented here revealed a special arrangement of APOA5 minor alleles in patients with different serum triglyceride ranges in Hungarians.

[Experiences with cardiac troponin assessments]. / Kardiális troponin méréssel szerzett tapasztalataink.

UNLABELLED: After the JESC/ACCC guideline (approved in year 2000), cardiac troponins became the first-line laboratory markers in the diagnosis of acute coronary syndrome. Since 2006, there is a hemodynamic laboratory in our Hospital and since July, 2007, there is a so called "one gate" Emergency Unit. AIM: Since the amount of the cardiac troponin assessments has risen, we aimed to analyze the background of this elevation, the results and the cause of the false positivity, as well. METHODS: We analyzed our cardiac troponin results assessed in the second half of year 2008. RESULTS: In this time we have had 2656 cardiac troponin examination in 1787 patients. 280 positive results were examined in 203 patients, but acute coronary syndrome was proved only in 110 patients. The remaining cases were false positive but only for detecting acute coronary syndrome, because many other diseases were proved in the background of these patients, and only one result was really (literally) false positive. CONCLUSIONS: Because of the very low rate of positive results we have to think about restriction of asking that examination. We emphasize that there are many non-acute coronary syndrome diseases with positive cardiac troponin results. This situation needs an urgent and close communication between the clinicians and the laboratory staff.

Galectin-2 3279TT variant protects against the lymphotoxin-alpha 252GG genotype associated ischaemic stroke.

OBJECTIVE: The galectin-2 protein is presumed to play a regulatory role in the intracellular trafficking of the lymphotoxin-alpha (LTA) cytokine. LTA is a pro-inflammatory factor, its 252GG homozygote variant is considered as a susceptibility factor for arteriosclerosis and cardiovascular diseases. By contrast, the galectin-2-encoding gene LGALS2 3279TT homozygote variant has been demonstrated to exert protection against myocardial infarction by reducing the transcriptional level of galectin-2, thereby leading to a reduced extracellular secretion of LTA. METHODS: In the present study, we examined whether the LGALS2 3279TT homozygote variant alone can influence the prevalence of ischaemic stroke, and whether it can interact somehow with the disadvantageous LTA 252GG homozygote variant. Genetic and clinical data of 385 ischemic stroke patients and 303 stroke and neuroimaging alteration-free controls were analysed. RESULTS: The combination of the LGALS2 3279TT and LTA 252GG homozygote was significantly less frequent in the ischemic stroke group (1.56%) than in the controls (5.94%, p<0.00187; overall stroke group: crude OR: 0.25, 95% CI: 0.1-0.64; adjusted OR: 0.03, 95% CI: 0.025-0.71). CONCLUSIONS: This finding suggests a gene-gene interaction.

Apolipoprotein A5 gene IVS3+G476A allelic variant confers susceptibility for development of ischemic stroke.

BACKGROUND: T-1131C, T1259C and IVS3+G476A are naturally occurring variants of the apolipoprotein A5 (APOA5) gene and their possible impact on the development of ischemic stroke was investigated in the present study. METHODS AND RESULTS: PCR-RFLP assays were used to determine the distributions of the APOA5 alleles in small-vessel, large-vessel and mixed subgroups of 378 patients and in 131 stroke-free control subjects. Increased triglyceride levels were found in subjects carrying -1131C, 1259C, IVS3+476A alleles in all stroke groups and in the controls. The -1131C and IVS3+476A alleles, but not the T1259C variant, showed significant accumulation in all stroke subgroups. Logistic regression analysis adjusted for age, gender, body mass index, total cholesterol level, ischemic heart disease, hypertension, diabetes mellitus, smoking-and drinking habits revealed that the IVS3+476A allele represents independent susceptibility factor for stroke (odds ratio for small-vessel: 4.748; large-vessel: 3.905; mixed: 2.926; overall: 3.644 at 95% confidence interval; p<0.05), we could also confirm the previously verified pathogenic role of the -1131C variant. CONCLUSIONS: All of the 3 APOA5 variants are associated with elevated triglycerides, but only the -1131C and the IVS3+476A alleles confer risk for all types of ischemic stroke; such an association could not be detected for the 1259C allele.

Apolipoprotein A5 gene C56G variant confers risk for the development of large-vessel associated ischemic stroke.

OBJECTIVES: Ischemic stroke is a suddenly developing temporary or often permanent damage of the brain. Several candidate genes have been shown to have an impact in the pathogenesis of stroke. The aim of our study was to investigate the possible association between the C56G variant of the apolipoprotein A5 (APOA5) gene and ischemic stroke. METHODS: PCR-RFLP assays were performed to detect the C56G alleles in 403 patients with classified stroke types and 171 controls. RESULTS: Triglyceride levels of subjects carrying 56G allele were elevated compared to the subjects with 56C allele in all stroke subgroups and in the controls. The serum total cholesterol levels did not differ between subjects with C or G alleles in each group. An accumulation of APOA5 56G allele was observed in the large-vessel associated stroke group compared to the healthy controls (10.9 vs. 5.6 %; p < 0.05), while its prevalence did not increase in any other stroke subgroups. Multivariate logistic regression analysis adjusted for differences in age, gender, BMI, serum total cholesterol levels, ischemic heart disease, hypertension, diabetes mellitus, smoking and drinking habits revealed that the APOA5 56G allele represents a susceptibility factor for large-vessel associated stroke (OR = 2.132 at 95 % CI; p < 0.05). CONCLUSION: The data presented here suggest that the 56G allele can confer risk exclusively for development of large-vessel associated stroke. Thereby, the 56G allele differs from the APOA5 T-1131C allelic variant, which has been previously identified as a risk factor for all subgroups of the stroke disease.

Apolipoprotein A5 IVS3+476A allelic variant associates with increased trigliceride levels and confers risk for development of metabolic syndrome in Hungarians.

BACKGROUND: Metabolic syndrome consists of multiple risk factors that are increasing the cardiovascular mortality. The T-1131C variant of the apolipoprotein A5 gene, associated with increased triglycerides, has been found to confer risk for cardiovascular diseases and metabolic syndrome. Because other naturally occurring variants of the gene also correlate with elevated triglycerides, the possible role of 2 common variants, the IVS3+G476A and T1259C, with metabolic syndrome was investigated. METHODS AND RESULTS: A total of 213 metabolic syndrome patients and 142 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Serum triglycerides were increased in carriers compared with non-carriers in both groups (p<0.001); serum cholesterol levels were similar in all genotypes. The IVS3+476A allele frequency was increased in metabolic syndrome patients compared with controls (8.05 vs 2.47%; p<0.05), whereas the 1259C allele frequency did not differ between the groups. Multiple logistic regression analyses adjusted for age, gender, serum total cholesterol, acute myocardial infarction and stroke revealed that the IVS3+476A variant confers risk for development of metabolic syndrome (odds ratio =3.529, 95% confidence interval 1.308-9.029, p=0.009), but the 1259C allele had no such an effect. CONCLUSIONS: Carrying the IVS3+473A allele is associated with elevated triglycerides and confers risk for development of metabolic syndrome, a combination that represents increased risk for development of atherogenic vascular diseases.

The combination of homozygous MTHFR 677T and angiotensin II type-1 receptor 1166C variants confers the risk of small-vessel-associated ischemic stroke.

Previous studies have suggested that both angiotensin II type-1 receptor (AT1R) 1166C and methylenetetrahydrofolate reductase (MTHFR) 677T variants can have disadvantageous effects on the small-vessel circulation under certain conditions. The purpose of this study was to analyze the possible consequences of the simultaneous distribution of these two genetic variants in different types of ischemic stroke. The genetic and clinical data on 357 ischemic stroke patients and 263 control subjects were analyzed by using univariate and logistic statistical approaches. Neither the MTHFR 677T nor the AT1R 1166C genetic variant alone conferred the risk of any subtype of ischemic stroke. The combination of the homozygous MTHFR 677TT genotype and at least one AT1R 1166C allele occurred more frequently in the ischemic stroke patients (8.68%) than in the controls (4.56%, p < 0.05). Specific subclassification of the patients revealed an accumulation of this combination in small-vessel-associated ischemic stroke (12.2%, p < 0.01); multivariate logistic regression analysis of the data confirmed this association, with an odds ratio of 2.66 (95% confidence interval, 1.28-7.89; p < 0.05). These findings suggest that the combination of these two genetic factors can contribute to the development of small-vessel cerebral infarcts. Although the exact mechanism of action is not known, addition of the unfavourable effects on the endothelial function can be presumed.

Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke.

The renin-angiotensin system plays an important role in the maintenance of blood pressure homeostasis. The angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), is a potent vasoconstrictor. On a pathophysiological basis, both ACE I/D and AT1R A1166C polymorphism lead to an enhanced activity of the angiotensin II-AT1R axis, thereby possibly contributing to circulatory disturbances. A mutually facilitatory effect may be presumed between the two polymorphisms. We examined whether this synergistic effect is involved in the evolution of different types of ischemic stroke. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. Atotal of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. The ACE D allele combined with the AT1R 1166C allele did not yield a risk of ischemic stroke. However, the co-occurrence of the homozygous ACE D/D and at least one AT1R 1166C allele was more frequent in the ischemic stroke group than in the control group (22.4 vs 11%, p < 0.005, OR, 2.33; 95% CI, 1.46-3.7). After specific subgroup analysis, this synergistic association was even stronger for small-vessel ischemic stroke (OR, 3.44; 95% CI, 1.9-6.24; p < 0.0005). Multivariate logistic regression analysis of the data confirmed this association (adjusted OR, 3.54, 95% CI, 1.88-7.16; p < 0.0005). Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. Genetic interactions might contribute to the altered functional network in renin-angiotensin system in vascular disorders.