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1.
The purpose of this study was to explore the association of the MCT1 gene Glu490Asp polymorphism (rs1049434) with athletic status and performance of endurance athletes. A total of 1,208 Brazilians (318 endurance athletes and 890 non-athletes) and 867 Europeans (315 endurance athletes and 552 non-athletes) were evaluated in a case–control approach. Brazilian participants were classified based on self-declared ethnicity to test whether the polymorphism was different between Caucasians and Afro-descendants. Moreover, 66 Hungarian athletes underwent an incremental test until exhaustion to assess blood lactate levels, while 46 Russian athletes had their maximum oxygen uptake (VO2max ) compared between genotypes. In the Brazilian cohort, the major T-allele was more frequent in Caucasian top-level competitors compared to their counterparts of lower competitive level (P = 0.039), and in Afro-descendant athletes compared to non-athletes (P = 0.015). Similarly, the T-allele was more frequent in European athletes (P = 0.029). Meta-analysis of the Brazilian and European cohorts confirmed that the T-allele is over-represented in endurance athletes (OR: 1.48, P = 0.03), especially when Afro-descendant athletes were included in the meta-analysis (OR: 1.58, P = 0.005). Furthermore, carriers of the T/T genotype accumulated less blood lactate in response to intense effort (P < 0.01) and exhibited higher VO2max (P = 0.04). In conclusion, the Glu490Asp polymorphism was associated with endurance athletic status and performance. Our findings suggest that, although ethnic differences may exist, the presence of the major T-allele (i.e., the Glu-490 allele) favours endurance performance more than the mutant A-allele (i.e., the 490-Asp allele).  相似文献   

2.
A healthy endothelium plays a core role in cardiovascu-lar control [1]. In the endothelial cell, nitric oxide (NO) issynthesized by the endothelial nitric oxide synthase (eNOS)encoded by a 26-exon gene (NOS 3) located on chromo-some 7 [2]. Besides its regulatory functions on vasomotortone and blood flow, endothelial NO is known to inhibitthe platelet activation and modulate migration and growthof the vascular smooth muscle [3]. Indirect evidence sug-gests that alterations of the NO pathwa…  相似文献   

3.
In the heart, angiotensin II has been suggested to regulate cardiac remodeling and promote cardiac hypertrophy. To examine this, we studied compound heterozygous mice, called angiotensin-converting enzyme (ACE) 1/8, in which one ACE allele is null, whereas the other ACE allele (the 8 allele) targets expression to the heart. In this model, cardiac ACE levels are about 15 times those of wild-type mice, and ACE expression is reduced or eliminated in other tissues. ACE 1/8 mice have 58% the cardiac ACE of a previous model, called ACE 8/8, but both ACE 1/8 and ACE 8/8 mice have ventricular angiotensin II levels about twofold those of wild-type controls. Despite equivalent levels of cardiac angiotensin II, ACE 1/8 mice do not develop the marked atrial enlargement or the conduction defects previously reported in the ACE 8/8 mice. Six-month-old ACE 1/8 mice have normal cardiac function, as determined by echocardiography and left ventricular catheterization, despite the elevated levels of angiotensin II. ACE 1/8 mice also have normal levels of connexin 43. Both wild-type and ACE 1/8 mice develop similar degrees of cardiac hypertrophy after aortic banding. These data suggest that a moderate increase of local angiotensin II production in the heart does not produce cardiac dysfunction, at least under basal conditions, and that, in response to aortic banding, cardiac hypertrophy is not augmented by a twofold increase of cardiac angiotensin II.  相似文献   

4.
American tegumentary leishmaniasis (ATL) is an infectious disease caused mostly by Leishmania (Viannia) braziliensis in Southeast Brazil. The clinical manifestations are vast, ranging from asymptomatic to severe mucosal leishmaniasis (ML). It has been suggested that variation of the pathogen does not fully explain the response spectrum and the variability of clinical manifestations. Previous data have shown that host genetics also play a role in disease outcome. Herein, we have tested the association of TNF, IL10, IL12 and MIF single nucleotide polymorphisms (SNPs) using a case-control study design including 110 cutaneous leishmaniasis (CL) patients and 682 healthy subjects. The genotype–phenotype correlation was also assessed using leishmania antigens to stimulate peripheral blood mononuclear cells obtained from cured CL patients. Results demonstrated that the MIF ?173C allele is associated with leishmaniasis outcome and also with lower levels of MIF in culture supernatants. Also, the TNF ?308AA genotype was statistically increased among leishmaniasis patients. The results showed here suggest that the lower levels of MIF produced by MIF ?173C carriers could influence the host–Leishmania interaction, favoring infection and disease progression. On the other hand, high TNF levels can contribute to tissue damage, consequently leading to skin lesions.  相似文献   

5.
Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general. However, the precise mechanism(s) by which coronary spasm occurs remains to be elucidated. Coronary spasm may arise from interactions between environmental and genetic factors. Endothelial derived nitric oxide (NO) has been implicated in the control of vascular tone. We have recently shown that both basal and acetylcholine (ACh)-induced NO activities are impaired in the coronary arteries of patients with coronary spasm. The purpose of this study has been to elucidate the possible variants that occur in the coding region of the endothelial nitric oxide synthase (eNOS) gene and that may be associated with coronary spasm. After initial screening in the entire 26 coding regions of the eNOS gene, we found a missense Glu298Asp variant in exon 7 in patients with coronary spasm. We subsequently performed a larger scale study involving 113 patients with coronary spasm and 100 control subjects, who were all diagnosed by intracoronary injection of ACh. The analysis revealed a significant difference in the distribution of the variant between the coronary spasm group (21.2%) and control group (9.0%; P=0.014 for dominant effect). Thus, we have found the missense Glu298Asp variant in the eNOS gene by the analysis of its entire 26 coding regions. The variant is significantly associated with coronary spasm. Received: 2 February 1998 / Accepted: 9 April 1998  相似文献   

6.
The cytoskeleton as classically defined for eukaryotic cells consists of three systems of protein filaments: the microtubules, the intermediate filaments, and the microfilaments. In mature striated muscle such as the heart of the adult mammal, these three types of cytoskeletal filaments are superimposed spatially on the myofilaments, a specialized system of contractile protein filaments. Each of these systems of protein filaments has the potential to respond in an adaptive or maladaptive manner during load-induced hypertrophic cardiac growth. However, the extent to which such hypertrophy is compensatory is also critically dependent on the type of hemodynamic overload that serves as the hypertrophic stimulus. Thus cardiac hypertrophy is not intrinsically maladaptive; rather, it is the nature of the inducing load rather than hypertrophy itself that is responsible, through effects on structural and/or regulatory proteins, for the frequent deterioration of initially compensatory hypertrophy into the congestive heart failure state. As one example reviewed here of this load specificity of maladaptation, increased microtubule network density is a persistent feature of severely pressure-overloaded, hypertrophied, and failing myocardium that imposes a primarily viscous load on active myofilaments during contraction.  相似文献   

7.
This study aimed to investigate the relationship between endothelial nitric oxide synthase Glu(298)Asp gene polymorphism and hemorheological parameters. Red blood cell (RBC) deformability, aggregation were measured using an ectacytometry, whole blood, plasma viscosities were determined by a viscometer. Restriction fragment length polymorphism was used to detect polymorphism. Plasma nitrite, nitrate concentrations were determined by Griess method. The genotype distribution of the control group was as follows: 50 (67.5%) GG, 21 (28.4%) GT, 3 (4.1%) TT. A 48 (57.8%) of the patients with CAD had GG, 28 (33.7%) GT, 7 (8.5%) of them TT genotype. RBC aggregation index of CAD patients with G allele was higher and t½ lower compared to controls carrying the same allele. The amplitude of RBC aggregation of healthy subjects with T allele, who are under increased cardiovascular risk was lower compared to control subjects with G allele. The results of this study indicate that, alterations in RBC aggregation seem to be a consequence of CAD, more than being a preexisting cause. Additionally, some compensatory mechanisms by causing decrements in RBC aggregation, may help regulation of circulation in healthy individuals with high cardiovascular risk.  相似文献   

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10.
Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the beta1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of >1,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the beta1 adrenergic receptor. For comparison, polymorphisms in the beta2 and beta3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated (P=.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the beta1 adrenergic receptor nor polymorphisms in the beta2 and beta3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1% (P<10-7).  相似文献   

11.
Cyclotides are a family of plant defense proteins with a unique cyclic backbone and cystine knot. Their remarkable stability under harsh thermal, enzymatic, and chemical conditions, combined with their range of bioactivities, including anti-HIV activity, underpins their potential as protein drug scaffolds. The vast majority of cyclotides possess a conserved glutamate residue in loop 1 of the sequence that is involved in a structurally important network of hydrogen bonds to an adjacent loop (loop 3). A single native cyclotide sequence, kalata B12, has been discovered that has an aspartic acid in this otherwise conserved position. Previous studies have determined that methylation of the glutamate or substitution with alanine abolishes the membrane disrupting activity that is characteristic of the family. To further understand the role of this conserved structural feature, we studied the folding, structure, stability, and activity of the natural aspartic acid variant kalata B12 and compared it to the prototypical cyclotide kalata B1, along with its glutamate to alanine or aspartate mutants. We show that the overall fold of kalata B12 is similar to the structure of other cyclotides, confirming that the cyclotide framework is robust and tolerant to substitution, although the structure appears to be more flexible than other cyclotides. Modification of the glutamate in kalata B1 or replacing the aspartate in kalata B12 with a glutamate reduces the efficiency of oxidative folding relative to the native peptides. The bioactivity of all modified glutamate cyclotides is abolished, suggesting an important functional role of this conserved residue. Overall, this study shows that the presence of a glutamic acid in loop 1 of the cyclotides improves stability and is essential for the membrane disrupting activity of cyclotides.  相似文献   

12.
AimsDisrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS.Main methodsVenous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5′-exonuclease allelic discrimination assay.Key findingsWe found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele.SignificanceDISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases.  相似文献   

13.
A neuronal NO synthase (NOS1) gene polymorphism is associated with asthma   总被引:2,自引:0,他引:2  
Recent family-based studies have revealed evidence for linkage of chromosomal region 12q to both asthma and high total serum immunoglobulin E (IgE) levels. Among the candidate genes in this region for asthma is neuronal nitric oxide synthase (NOS1). We sought a genetic association between a polymorphism in the NOS1 gene and the diagnosis of asthma, using a case-control design. Frequencies for allele 17 and 18 of a CA repeat in exon 29 of the NOS1 gene were significantly different between 490 asthmatic and 350 control subjects. Allele 17 was more common in the asthmatics (0.83 vs 0.76, or 1.49 [95% CI 1.17-1.90], P = 0.013) while allele 18 was less common in the asthmatics (0.06 vs 0.12, or 0.49 [95% CI 0.34-0. 69], P = 0.0004). To confirm these results we genotyped an additional 1131 control subjects and found the frequencies of alleles 17 and 18 to be virtually identical to those ascertained in our original control subjects. Total serum IgE was not associated with any allele of the polymorphism. These findings provide support, from case-control association analysis, for NOS1 as a candidate gene for asthma.  相似文献   

14.
BackgroundThe potentially functional polymorphism, rs909253 (+252 G>A), in the intron region of the LT-α (TNF-β) gene has been implicated in the risk of gastric cancer (GC) in some individually published studies, but others have shown inconsistent and inconclusive results.MethodsWe conducted a meta-analysis to assess the association between the lymphotoxin-α gene (LTA) + 252 (G>A) polymorphism and gastric cancer susceptibility.ResultsWe demonstrate that there were no significant associations in single-locus analysis between the polymorphism of LTA and gastric cancer risk in all subjects; however, when studies were stratified by ethnicity, these polymorphisms of LTA were found to be associated with a significant cancer risk in different genetic models in an Asian population (heterozygote [GA genotype] comparison: odds ratio [OR] = 1.29, 95% confidence interval [CI]: 1.01–1.65, P = 0.038) in which the risk in the subjects was more than 70% (12 studies with 2074 cases and 3690 controls). Moreover, the susceptibility to gastric carcinogenesis has a substantial influence on the population-attributable risk by modulating the effects of environmental risk factors such as Helicobacter pylori infection (OR = 1.77, 95%CI: 1.05–2.99, P = 0.032).ConclusionsThe present meta-analysis results suggest that the LTA rs909253 GA genotype is a possible risk factor for developing gastric cancer in the Asian population, especially those with H. pylori infection.  相似文献   

15.

Introduction

Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association.

Methods

PCR-based assays were used to determine the genotypes of TGFB1 SNPs including TGFB1-509 C/T (rs1800469, in the promoter region), +868 T/C (rs1800470, in exon 1) and +913 G/C (rs1800471, in exon 1) in 414 subjects with established RA. Genotyping for the +868 SNP was also carried out on a second study population of RA patients (n = 259) with early disease. Serum levels of TGF-beta1 were measured using a commercial ELISA kit. Smoking history and IHD/MI status were obtained on each patient. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses.

Results

The heterozygous genotype of TGFB+868 was associated with an increased risk of IHD (OR 2.14, 95% CI 1.30 - 3.55) and MI (OR 2.42, 95% CI 1.30-4.50), compared to the homozygous genotypes combined. Smoking was an independent risk for IHD and MI, and evidence of interaction between smoking and TGFB+868 was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the TGFB1+868 TC genotype and smoking (OR 2.75, 95% CI 1.59-4.75; and OR 2.58 95% CI 1.33-4.99, respectively), independent of other cardiovascular risk factors. The association of the +868 TC genotype and evidence of +868 TC-smoking interaction with IHD were replicated in a second population of RA patients with early disease. Serum TGF-beta1 levels were not associated with TGFB1 genetic variations, smoking or IHD/MI status.

Conclusions

Interaction between smoking and polymorphism in the TGFB1 gene may influence the risk of IHD and MI in patients with RA.  相似文献   

16.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Cardiovascular disease (CVD) is common and a major cause of mortality. Studies on cardiovascular morbidity are abundant, whereas mortality studies focusing on cardiovascular outcomes are scarce. The aim of this study was to investigate causes of death and baseline predictors of overall (OM), non-vascular (N-VM), and specifically cardiovascular (CVM) mortality in SLE, and to evaluate systematic coronary risk evaluation (SCORE).

Methods

208 SLE patients were included 1995-1999 and followed up after 12 years. Clinical evaluation, CVD risk factors, and biomarkers were recorded at inclusion. Death certificates and autopsy protocols were collected. Causes of death were divided into CVM (ischemic vascular and general atherosclerotic diseases), N-VM and death due to pulmonary hypertension. Predictors of mortality were investigated using multivariable Cox regression. SCORE and standardized mortality ratio (SMR) were calculated.

Results

During follow-up 42 patients died at mean age of 62 years. SMR 2.4 (CI 1.7-3.0). 48% of deaths were caused by CVM. SCORE underestimated CVM but not to a significant level. Age, high cystatin C levels and established arterial disease were the strongest predictors for all- cause mortality. After adjusting for these in multivariable analyses, only smoking among traditional risk factors, and high soluble vascular cell adhesion molecule-1 (sVCAM-1), high sensitivity C-reactive protein (hsCRP), anti-beta2 glycoprotein-1 (abeta2GP1) and any antiphospholipid antibody (aPL) among biomarkers, remained predictive of CVM.

Conclusion

With the exception of smoking, traditional risk factors do not capture the main underlying risk factors for CVM in SLE. Rather, cystatin C levels, inflammatory and endothelial markers, and antiphospholipid antibodies (aPL) differentiate patients with favorable versus severe cardiovascular prognosis. Our results suggest that these new biomarkers are useful in evaluating the future risk of cardiovascular mortality in SLE patients.  相似文献   

17.
We have previously demonstrated that progressive development of absence of meal-induced insulin sensitization (AMIS) leads to postprandial hyperglycemia, compensatory hyperinsulinemia, resultant hyperlipidemia, increased oxidative stress, and obesity, progressing to syndrome X in aging rats. The present study tested the hypothesis that progressive development of AMIS in aging rats further resulted in deterioration in cardiac performance. Anesthetized male Sprague-Dawley rats were tested at 9, 26, and 52 wk to determine their dynamic response to insulin and cardiac function. Dynamic insulin sensitivity was determined before and after atropine to quantitate hepatic insulin sensitizing substance (HISS)-dependent and -independent insulin action. Cardiac performance was evaluated using a Millar pressure-volume conductance catheter system. AMIS developed with age, as demonstrated by significant decrease in HISS-dependent insulin action, and this syndrome was increased by sucrose supplementation and inhibited by the antioxidant treatment. Associated with progressive development of AMIS, aging rats showed impaired cardiac performance, including the reduction in cardiac index, heart rate, dP/dt(max), dP/dt(min), ejection fraction and decreased slope of left ventricular end-systolic pressure-volume relationship, and increased relaxation time constant of left ventricular pressure as well as increased left ventricular end-diastolic pressure. Total peripheral vascular resistance also increased with age. Sucrose supplementation and antioxidant treatment, respectively, potentiated and attenuated cardiac dysfunction associated with age. In addition, poor cardiac performance correlated closely with the development of AMIS. These results indicate that AMIS is the first metabolic defect that leads to homeostatic disturbances and dysfunctions, including cardiovascular diseases.  相似文献   

18.
This study aimed to investigate the association between PASD8 gene and cancers. For 1772 C/T polymorphism (rs11549465), it included 5552 cases and 8044 controls, and for 1790 G/A (rs11549467), 3381 cases and 5830 controls. The allele-analysis results showed that 1772 C/T (rs11549465) was significantly associated with cancers (OR: 1.177, 95% CI: 1.011–1.369, p = 0.035). And results of genotype-analysis indicated that 1790 G/A (rs11549467) had a significant relationship with cancers. (OR: 0.736, 95% CI: 0.595–0.910, p = 0.005). For 1790 G/A (rs11549467), the association was significant when subdivided by different kinds of cancers. And no association existed when subdivided into population-type subgroups. In conclusion, PASD8 gene played an important role in the development of cancers.  相似文献   

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