Elevated plasma total homocysteine (tHcy), low B-vitamin intake, and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease (CHD). More prospective studies are ...needed.
We used a prospective case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center-adjusted CHD incidence was associated positively (P<0.05) with tHcy in women but not men, and CHD was associated negatively (P<0.05) with plasma folate (women only), plasma pyridoxal 5'-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5'-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C677T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene.
Our prospective findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major, independent, causative risk factor for CHD. Our findings point more strongly to the possibility that vitamin B6 offers independent protection. Randomized trials, some of which are under way, are needed to better clarify the interrelationships of tHcy, B vitamins, and cardiovascular disease.
Although many case-control studies have investigated the association between the SLC11 A1 gene polymorphisms and tuberculosis (TB) susceptibility, results were conflicting due to limited power. We ...reviewed the literature systematically by means of meta-analysis, provided a quantitative summary estimate on the association with TB, and examined some sources of between-study heterogeneity.
We searched databases (MEDLINE, PUBMED and OVID) from January 1995 to December 2004 using 'gene' or 'SLC11A1' or 'NRAMP1', in combination with 'tuberculosis', performed a manual search of citations from relevant original studies and review articles, or corresponded with authors.
The summary ORs for studies with 3'UTR, D543N, INT4 and 5'(GT)n loci allele variants in the SLC11A1 gene were 1.33 (95%CI 1.08-1.63), 1.67 (95%CI 1.36-2.05), 1.14 (95%CI 0.96-1.35) and 1.32 (95%CI 1.03-1.68), respectively, compared with their corresponding common alleles. The pooled ORs by sub-group analyses for the four loci described above were 1.20 (95%CI 0.86-1.68), 1.69 (95%CI 1.14-2.50), 1.50 (95%CI 1.17-1.91), and 1.31 (95%CI 1.05-1.64) in subjects of African descent, 1.46 (95%CI 1.10-1.94), 1.65 (95%CI 1.29-2.12), 0.91 (95%CI 0.66-1.25) and 1.86 (95%CI 1.33-2.62) in Asian subjects, 1.81 (95%CI 0.66-4.93), 1.79 (95%CI 0.72-4.47), 0.87 (95%CI 0.61-1.22) and 1.02 (95%CI 0.35-2.99) in European subjects.
Polymorphisms at the four loci had no statistically significant association between the SLC11A1 variants and susceptibility to TB in subjects of European descent, while they showed a statistically significant association in Asian subjects (except the INT4 variant), African subjects (except the 3'UTR variant) and the population as a whole (except the INT4 variant).
The glutathione peroxidase 1 gene (
GPX1) and the manganese superoxide dismutase gene (
MnSOD) encode the main antioxidant enzymes that detoxify endogenous reactive oxygen species involved in ...carcinogenesis. Polymorphisms of
GPX1 and
MnSOD genes, and the risk of transitional cell cancer of the bladder were tested.
Genotypes of the leucine (
Leu) to proline (
Pro) polymorphism at codon 198 of
GPX1, the alanine (
Ala) to Valine (
Val) polymorphism in exon 2 and the isoleucine to threonine polymorphism at codon 56 of
MnSOD were determined by a polymerase chain reaction-restriction fragment length polymorphism technique in 213 patients and 209 normal controls.
There was a significant difference in
GPX1 genotype frequency between the case and control groups (p = 0.001). The adjusted OR for bladder cancer was 2.63 for the
Pro/Leu genotype compared with the
Pro/Pro genotype (95% CI 1.45 to 4.75, p = 0.001). Compared with the
Pro/Pro genotype the
Pro/Leu genotype was significantly associated with advanced tumor stage (Ta-1 vs T2–4, OR 2.58, 95% CI 1.07 to 6.18, p = 0.034) but not with tumor grade. Analysis of the
MnSOD polymorphism provided no significant results. However, in men with at least 1
Ala MnSOD allele the risk associated with the
Pro/Leu GPX1 genotype increased up to 6.31 (95% CI 1.28 to 31.24, p = 0.024).
The
GPX1 Pro/Leu genotype may significantly increase the risk of bladder cancer and the increased risk may be modified by the Ala-9Val
MnSOD polymorphism. The
GPX1 genotype may further affect the disease status of bladder cancer.
Objectives The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of ...myocardial ischemia. Background A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks of the cardiomyocyte. Methods The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed using CAR haploinsufficient (CAR+/− ) mice. Results In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR+/− mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR+/− hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR+/− myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV 1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV 1.5. Conclusions CAR is a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease.
To examine the association between variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in men and women.
In 1780 unrelated members of the community-based ...Framingham Heart Study offspring cohort, systolic blood pressure and diastolic blood pressure were measured over a total of six examination cycles encompassing 24 years of follow-up. Multivariate regression analyses were used to assess the relation between untreated cross-sectional and longitudinal blood pressure and polymorphisms at the estrogen receptor-alpha (ESR1), estrogen receptor-beta (ESR2), aromatase (CYP19A1), and nuclear receptor coactivator 1 (NCOA1) genes after adjustment for common risk factors.
In men, systolic blood pressure and pulse pressure (systolic blood pressure minus diastolic blood pressure) were associated with two polymorphisms in ESR1, while pulse pressure was also associated with variations in NCOA1 and CYP19A1. Polymorphisms in ESR1, CYP19A1, and NCOA1 were associated with diastolic blood pressure in women.
Although the underlying relations between genes involved in estrogen action and hypertension remain to be completely understood, our findings provide suggestive evidence of gender-specific contributions of estrogen-related genes to blood pressure variation. As no correction for multiple testing was performed in the analyses, we view these results as suggestive and not definitive. Further studies are warranted to confirm these results using a comprehensive set of polymorphisms in order to shed more light on the involvement of estrogen in blood pressure regulation.
The chromogranin/secretogranin proteins are costored and coreleased with catecholamines from secretory vesicles in chromaffin cells and noradrenergic neurons. Chromogranin A (CHGA) regulates ...catecholamine storage and release through intracellular (vesiculogenic) and extracellular (catecholamine release–inhibitory) mechanisms.
CHGA is a candidate gene for autonomic dysfunction syndromes, including intermediate phenotypes that contribute to human hypertension. Here, we show a surprising pattern of
CHGA variants that alter the expression and function of this gene, both in vivo and in vitro. Functional variants include both common alleles that quantitatively alter gene expression and rare alleles that qualitatively change the encoded product to alter the signaling potency of CHGA-derived catecholamine release–inhibitory catestatin peptides.
Abstract Background: The 9p21 region is the most relevant locus associated with coronary heart disease in different populations. However, there are no studies that prove that this region is a risk ...factor in the Venezuelan population. Objectives: To analyze whether or not the 9p21 rs1333049 polymorphism is a risk factor for acute myocardial infarction (AMI) in Venezuelan patients, as well as to investigate its correlation with cardiovascular risk factors (CVRF), age of occurrence, type and severity of infarction, and the correlation of the rs10757274 polymorphism with severity of coronary artery disease. Methods: This was an association study, including 487 unrelated Venezuelan individuals, grouped in 354 patients with AMI and 133 controls. The rs1333049 and rs10757274 polymorphisms were determined using the polymerase chain reaction (PCR) technique with sequence-specific primers. The analysis of association was determined using the SNPStats tool. The continuous variable description and the correlations were performed using the SPSS statistical software. Significance was established at p<0.05. Results: A positive correlation was observed between the rs1333049 polymorphism and the presence of hypertension ( r: 0.145, p: 0.006), and between hypertension and heart infarction ( r: 0.318, p: <0.0001). A positive correlation was found between the rs10757274 polymorphism and the number of coronary vessels that presented obstructive lesions in patients aged ≤ 55 years ( r: 0.276, p: 0.0078). Conclusion: The rs1333049 polymorphism at the 9p21 locus is correlated with hypertension in Venezuelan patients, while the rs10757274 polymorphism is associated with the progression of coronary atherosclerosis, suggested by the correlation with the number of coronary vessels that presented significant obstructive lesions.
Previous studies in population genetics have proposed that the Y-chromosomal (Y-DNA) haplogroup D ancestor likely originated from Africa. The haplogroup D branch next started Out-of-Africa migration, ...rapidly expanded across Eurasia, and later diversified in East Asia. Y-DNA haplogroup D-M55, one of the branches of haplogroup D, is only found in modern Japanese males, suggesting that individuals with Y-DNA haplogroup D migrated from the Eurasian continent. Based on previous observations, Y-DNA haplogroup D is expected to be associated with some male characteristics including personality. Therefore, this study investigated whether the Y-DNA haplogroup D-M55 is associated with several physiological and psychological characteristics, including exploratory motivation and human relationship-related perception. We recruited Japanese young adult males and females and investigated the association between Y-DNA haplogroup D-M55, physiological body mass index (BMI), and several psychological parameters perceived number of close friends, behavioral inhibition system/behavioral activation system (BIS/BAS), perceived happiness, and perceived loneliness. The results indicated that males with haplogroup D-M55 had a higher BMI and more close friends, compared with non-carrier males. Additional multiple regression analyses, which tested the hypothesis that haplogroup D-M55 predicts BMI and perceived number of close friends, confirmed our hypothesis, even after controlling for the potentially confounding variables of age and sex. We also analyzed the gene-gene interaction between haplogroup D-M55 and an autosomal gene polymorphism associated with BMI and human relationships, such as the dopamine D2 receptor gene (
: rs1800497). Results showed gene-gene interactions between haplogroups D-M55 and
in BMI. Based on these findings, it is demonstrated that Y-DNA haplogroup D is associated with human personality.
Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor ...necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.
Recent epidemiologic studies have suggested that genetic polymorphisms in the cytochrome P-450 1A1 gene (CYP1A1) may affect the relation between environmental exposure to polychlorinated biphenyls ...(PCBs) and breast cancer risk. The authors report results from a case-control study evaluating the potential effect of gene-environment interaction between CYP1A1 and serum PCB levels on breast cancer risk among Caucasian women in Connecticut. The study included 374 case women with histologically confirmed breast cancer and 406 noncancerous controls with information on both serum PCB level and CYP1A1 genotype (1999–2002). Compared with women who had the homozygous wild-type CYP1A1 m2 genotype, significantly increased risks of breast cancer were found for women with the CYP1A1 m2 variant genotype (odds ratio (OR) = 2.1, 95% confidence interval (CI): 1.1, 3.9), especially postmenopausal women (OR = 2.4, 95% CI: 1.1, 5.0). Risks associated with the CYP1A1 m2 variant genotype were highest for all women (OR = 3.6, 95% CI: 1.5, 8.2) and postmenopausal women (OR = 4.3, 95% CI: 1.6, 12.0) with higher serum PCB levels (611–2,600 ng/g). The CYP1A1 m1 and m4 genotypes were not associated with breast cancer risk independently or in combination with PCB exposure. In summary, the CYP1A1 m2 genetic polymorphism was associated with increased risk of female breast cancer and may modify the relation between PCB exposure and breast cancer risk.
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